Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

ABSTRACT

The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or optionally, at least one therapeutic agent, such as, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B 4  (LTB 4 ) receptor antagonists, leukotriene A 4  (LTA 4 ) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H 2 antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics,  Helicobacter pylori  inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

RELATED APPLICATIONS

[0001] This application is a divisional of U.S. application No.09/741,816, filed Dec. 22, 2000, now allowed, which claims priority toU.S. Provisional Application No. 60/171,623 filed Dec. 23, 1999 and U.S.Provisional Application No. 60/226,085 filed Aug. 18, 2000.

FIELD OF THE INVENTION

[0002] The present invention describes novel nitrosated and/ornitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositionscomprising at least one nitrosated and/or nitrosylated cyclooxygenase 2(COX-2) inhibitor, and, optionally, at least one compound that donates,transfers or releases nitric oxide, stimulates endogenous synthesis ofnitric oxide, elevates endogenous levels of endothelium-derived relaxingfactor or is a substrate for nitric oxide synthase, and/or at least onetherapeutic agent. The present invention also provides novelcompositions comprising at least one COX-2 inhibitor. The presentinvention also provides methods for treating inflammation, pain andfever; for treating and/or improving the gastrointestinal properties ofCOX-2 inhibitors; for facilitating wound healing; for treating and/orpreventing renal toxicity; and for treating and/or preventing otherdisorders resulting from elevated levels of cyclooxygenase-2.

BACKGROUND OF THE INVENTION

[0003] Nonsteroidal anti-inflammatory compounds (NSAIDs) are widely usedfor the treatment of pain, inflammation, and acute and chronicinflammatory disorders such as osteoarthritis and rheumatoid arthritis.These compounds inhibit the activity of the enzyme cyclooxygenase (COX),also known as prostaglandin G/H synthase, which is the enzyme thatconverts arachidonic acid into prostanoids. The NSAIDs also inhibit theproduction of other prostaglandins, especially prostaglandin G₂,prostaglandin H₂ and prostaglandin E₂, thereby reducing theprostaglandin-induced pain and swelling associated with the inflammationprocess. The chronic use of NSAIDs has been associated with adverseeffects, such as gastrointestinal ulceration and renal toxicity. Theundesirable side effects are also due to the inhibition of prostaglandinin the affected organ.

[0004] Recently two isoforms of cyclooxygenase, encoded by two distinctgenes (Kujubu et al, J. Biol. Chem., 266, 12866-12872 (1991)), have beenidentified—a constitutive form, cyclooxygenase-1 (COX-1), and aninductive form, cyclooxygenase-2 (COX-2). It is thought that theantiinflammatory effects of NSAIDs are mediated by the inhibition ofCOX-2, whereas the side effects seem to be caused by the inhibition ofCOX-1. The NSAIDs currently on the market either inhibit both isoformsof COX with little selectivity for either isoform or are COX-1selective. Recently compounds that are selective COX-2 inhibitors havebeen developed and marketed. These selective COX-2 inhibitors have thedesired therapeutic profile of an antiinflammatory drug without theadverse effects commonly associated with the inhibition of COX-1.However, these compounds can result in dyspepsia and can causegastropathy (Mohammed et al, N. Engl. J. Med., 340(25) 2005 (1999)).

[0005] Selective COX-2 inhibitors are disclosed in, for example, U.S.Pat. Nos. 5,681,842, 5,750,558, 5,756,531, 5,776,984 and in WO 97/41100,WO 98/39330, WO 99/10331, WO 99/10332 and WO 00/24719 assigned to AbbottLaboratories; and in WO 98/50075, WO 00/29022 and WO 00/29023 assignedto Algos Pharmaceutical Corporation; and in WO 99/15205 assigned toAlmirall Prodesfarma S.A.; and in U.S. Pat. No. 5,980,905 assigned toAMBI Inc.; and in U.S. Pat. No. 5,945,538 assigned to American CyanamidCompany; and in U.S. Pat. Nos. 5,776,967, 5,824,699, 5,830,911 and in WO98/04527 and WO 98/21195 assigned to American Home Products Corporation;and in WO 98/22442 assigned to Angelini Richerche S. P. A. SocietaConsortile; and in U.S. Pat. No. 6,046,191 and in WO 99/18960 and WO00/00200 assigned to Astra Pharmaceuticals Ltd.; and in U.S. Pat. No.5,905,089 assigned to Board of Supervisors of Louisiana StateUniversity; and in WO 97/13767 assigned to Chemisch PharmazeutischeForschungsgesellschaft MBH; and in WO 98/57924 and WO 99/61436 assignedto Chugai Seiyaku Kabushiki Kaisha; and in WO 00/13685 assigned toCornell Research Foundation Inc.; and in WO 96/10021 assigned to The DuPont Merck Pharmaceutical Company; and in EP 0 087 629 B1 assigned to E.I. Du Pont de Nemours and Company; and in WO 99/13799 assigned toEuro-Celtique; and in U.S. Pat. No. 5,134,142 and in WO 91/19708, WO97/13755, WO 99/15505, WO 99/25695 and in EP 0 418 845 B1 and EP 0 554829 A2 assigned to Fujisawa Pharmaceutical Co. Ltd.; and in U.S. Pat.Nos. 5,344,991, 5,393,790, 5,434,178, 5,466,823, 5,486,534, 5,504,215,5,508,426, 5,510,496, 5,516,907, 5,521,207, 5,563,165, 5,580,985,5,596,008, 5,616,601, 5,620,999, 5,633,272, 5,643,933, 5,668,161,5,686,470, 5,696,143, 5,700,816, 5,719,163, 5,753,688, 5,756,530,5,760,068, 5,859,257, 5,908,852, 5,935,990, 5,972,986, 5,985,902,5,990,148, 6,025,353, 6,028,072, 6,136,839 and in WO 94/15932, WO94/27980, WO 95/11883, WO 95/15315, WO 95/15316, WO 95/15317, WO95/15318, WO 95/21817, WO 95/30652, WO 95/30656, WO 96/03392, WO96/03385, WO 96/03387, WO 96/03388, WO 96/09293, WO 96/09304, WO96/16934, WO 96/25405, WO 96/24584, WO 96/24585, WO 96/36617, WO96/38418, WO 96/38442, WO 96/41626, WO 96/41645, WO 97/11704, WO97/27181, WO 97/29776, WO 97/38986, WO 98/06708, WO 98/43649, WO98/47509, WO 98/47890, WO 98/52937, WO 99/22720, WO 00/23433, WO00/37107, WO 00/38730, WO 00/38786 and WO 00/53149 assigned to G. D.Searle & Co.; and in WO 96/31509, WO 99/12930, WO 00/26216 and WO00/52008 assigned to Glaxo Group Limited; and in EP 1 006 114 A1 and inWO 98/46594 assigned to Grelan Pharmaceutical Co. Ltd.; and in WO97/34882 assigned to Grupo Farmaceutico Almirall; and in WO 97/03953assigned to Hafslund Nycomed Pharma AG; and in WO 98/32732 assigned toHoffmann-La Roche AG; and in U.S. Pat. Nos. 5,945,539, 5,994,381,6,002,014 and in WO 96/19462, WO 96/19463 and in EP 0 745 596 A1assigned to Japan Tobacco, Inc.; and in U.S. Pat. Nos. 5,686,460,5,807,873 and in WO 97/37984, WO 98/05639, WO 98/11080 and WO 99/21585assigned to Laboratories USPA; and in WO 99/62884 assigned toLaboratories Del Dr. Esteve, S. A.; and in WO 00/08024 assigned toLaboratorios S.A.L.V.A.T., S. A.; and in U.S. Pat. Nos. 5,585,504,5,840,924, 5,883,267, 5,925,631, 6,001,843, 6,080,876 and in WO97/44027, WO 97/44028, WO 97/45420, WO 98/00416, WO 98/47871, WO99/15503, WO 99/15513, WO 99/20110, WO 99/45913, WO 99/55830, WO00/25779 and WO 00/27382 assigned to Merck & Co. Inc.; and in U.S. Pat.Nos. 5,409,944, 5,436,265, 5,474,995, 5,536,752, 5,550,142, 5,510,368,5,521,213, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 5,677,318,5,691,374, 5,698,584, 5,710,140, 5,733,909, 5,789,413, 5,817,700,5,840,746, 5,849,943, 5,861,419, 5,981,576, 5,994,379, 6,020,343,6,071,936, 6,071,954 and in EP 0 788 476 B1, EP 0 863 134 A1, EP 0 882016 B1 and in WO 94/20480, WO 94/13635, WO 94/26731, WO 95/00501, WO95/18799, WO 96/06840, WO 96/13483, WO 96/19469, WO 96/21667, WO96/23786, WO 96/36623, WO 96/37467, WO 96/37468, WO 96/37469, WO97/14691, WO 97/16435, WO 97/28120, WO 97/28121, WO 97/36863, WO98/03484, WO 98/41511, WO 98/41516, WO 98/43966, WO 99/14194, WO99/14195, WO 99/23087, WO 99/41224 and WO 00/68215 assigned to MerckFrosst Canada & Co., and in WO 99/59635 assigned to Merck Sharp & DohmeLimited; and in U.S. Pat. No. 5,380,738 assigned to Monsanto Company;and in WO 00/01380 assigned to A. Nattermann & Co.; and in WO 99/61016assigned to Nippon Shinyaku Co. Ltd.; and in WO 99/33796 assigned toNissin Food Products Co. Ltd.; and in WO 99/11605 assigned to NovartisAG; and in WO 98/33769 assigned to Nycomed Austria GMBH; and in U.S.Pat. Nos. 6,077,869 and 6,083,969 and in WO 00/51685 assigned toOrtho-McNeil Pharmaceutical, Inc.; and in U.S. Pat. No. 5,783,597assigned to Ortho Pharmaceutical Corporation; and in WO 98/07714assigned to Oxis International Inc.; and in WO 00/10993 assigned toPacific Corporation; and in EP 0 937 722 A1 and in WO 98/50033, WO99/05104, WO 99/35130 and WO 99/64415 assigned to Pfizer Inc.; and in WO00/48583 assigned to Pozen Inc.; and in U.S. Pat. No. 5,908,858 assignedto Sankyo Company Limited; and in WO 97/25045 assigned to SmithKlineBeecham Corporation; and in U.S. Pat. No. 5,399,357 assigned to TakedaChemical Industries, Ltd.; and in WO 99/20589 assigned to The Universityof Sydney; and in U.S. Pat. No. 5,475,021 and WO 00/40087 assigned toVanderbilt University; and in WO 99/59634 assigned to WakamotoPharmaceutical Co. Ltd., the disclosures of each of which areincorporated by reference herein in their entirety.

[0006] There is still a need in the art for COX-2 inhibitor compoundsthat have gastroprotective properties, facilitate wound healing,decreased renal toxicity and dyspepsia, and that can be used at lowdosages. The present invention is directed to these, as well as other,important ends.

SUMMARY OF THE INVENTION

[0007] The present invention provides novel nitrosated and/ornitrosylated COX-2 inhibitors, which are COX-2 inhibitors linked to atleast one nitrogen monoxide group (NO), and/or at least one nitrogendioxide group (NO₂) (i.e., nitrosylated and/or nitrosated group,respectively). The resulting compounds are potent analgesics, haveantiinflammatory properties and have an unexpected potential forfacilitating wound healing. The novel compounds also have unexpectedproperties in the treatment and/or prevention of renal toxicity. TheCOX-2 inhibitors can be nitrosated and/or nitrosylated through one ormore sites, such as oxygen (hydroxyl condensation), sulfur (sulfhydrylcondensation) and/or nitrogen. The COX-2 inhibitor can be, for example,a sulfonamide containing 1,5-diarylpyrazole derivative, such as, forexample, CELEBREX®(4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide,Celecoxib). The COX-2 inhibitor can also be, for example, amethylsulfonylphenyl-furanone derivative, such as, for example,Rofecoxib (VIOXX®,4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone). The presentinvention also provides compositions comprising such compounds in apharmaceutically acceptable carrier.

[0008] The present invention is also based on the discovery thatadministering at least one nitrosated and/or nitrosylated COX-2inhibitor and at least one nitric oxide donor reduces thegastrointestinal distress induced by COX-2 inhibitors. A nitric oxidedonor is a compound that contains a nitric oxide moiety and whichreleases or chemically transfers nitric oxide to another molecule.Nitric oxide donors include, for example, S-nitrosothiols, nitrites,nitrates, N-oxo-N-nitrosamines, and substrates of the various isozymesof nitric oxide synthase. Thus, another aspect of the invention providescompositions comprising at least one COX-2 inhibitor that is substitutedwith at least one NO and/or NO₂ group (i.e., nitrosylated and/ornitrosated), and at least one compound that donates, transfers orreleases nitric oxide as a charged species, i.e., nitrosonium (NO⁺ _(.))or nitroxyl (NO−), or as the neutral species, nitric oxide (NO.), and/orstimulates endogenous production of nitric oxide or EDRF in vivo and/oris a substrate for nitric oxide synthase.

[0009] Yet another aspect of the invention provides compositionscomprising at least one COX-2 inhibitor that is substituted with atleast one NO and/or NO₂ group (i.e., nitrosylated and/or nitrosated),and, optionally, at least one compound that donates, transfers orreleases nitric oxide as a charged species, i.e., nitrosonium (NO⁺) ornitroxyl (NO−), or as the neutral species, nitric oxide (NO.), and/orstimulates endogenous production of nitric oxide or EDRF in vivo and/oris a substrate for nitric oxide synthase, and, optionally, at least onetherapeutic agent, including but not limited to, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG CoA inhibitors, H₂,antagonists, antineoplastic agents, antiplatelet agents, decongestants,diuretics, sedating or non-sedating anti-histamines, inducible nitricoxide synthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike.

[0010] Another aspect of the invention provides compositions comprisingat least one parent COX-2 inhibitor and at least one compound thatdonates, transfers or releases nitric oxide as a charged species, i.e.,nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species, nitricoxide (NO.), and/or stimulates endogenous production of nitric oxide orEDRF in vivo and/or is a substrate for nitric oxide synthase, and,optionally, at least one therapeutic agent, including but not limitedto, steroids, nonsteroidal antiinflammatory compounds (NSAID),5-lipoxygenase (5-LO) inhibitors, leukotriene B₄ (LTB₄) receptorantagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists,HMG CoA inhibitors, H₂ antagonists, antineoplastic agents, antiplateletagents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and the like.

[0011] Yet another aspect of the present invention provides methods fortreating and/or preventing inflammation, pain and fever; for treatingand/or improving gastrointestinal properties of COX-2 inhibitors; forfacilitating wound healing; for treating and/or preventing renaltoxicity; and for treating and/or preventing COX-2 mediated disorders(i.e., disorders resulting from elevated levels of COX-2) in a patientin need thereof which comprises administering to the patient atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor compound, and, optionally, at least onecompound that donates, transfers or releases nitric oxide as a chargedspecies, i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutralspecies, nitric oxide (NO.), and/or stimulates endogenous production ofnitric oxide or EDRF in vivo and/or is a substrate for nitric oxidesynthase and/or stimulates endogenous production of NO or EDRF in vivoand/or is a substrate for nitric oxide synthase (i.e., NO donors). Themethod can optionally further comprise the administration of at leastone therapeutic agent, such as, for example, steroids, nonsteroidalantiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and mixtures thereof. In this aspect of theinvention, the methods can involve administering nitrosated and/ornitrosylated COX-2 inhibitors, administering nitrosated and/ornitrosylated COX-2 inhibitors and NO donors, administering nitrosatedand/or nitrosylated COX-2 inhibitors and therapeutic agents, oradministering nitrosated and/or nitrosylated COX-2 inhibitors, NO donorsand therapeutic agents. The nitrosated and/or nitrosylated COX-2inhibitors, nitric oxide donors, and/or therapeutic agents can beadministered separately or as components of the same composition in oneor more pharmaceutically acceptable carriers.

[0012] Another aspect of the present invention provides methods fortreating inflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 inhibitors; for facilitating woundhealing; for treating and/or preventing renal toxicity; and for treatingand/or preventing other cyclooxygenase-2 mediated disorders comprisingadministration of at least one parent COX-2 inhibitor and at least onenitric oxide donor, and, optionally, at least one therapeutic agent.

[0013] Yet another aspect of the present invention provides kitscomprising at least one nitrosated and/or nitrosylated COX-2 inhibitor,and, optionally, at least one compound that donates, transfers orreleases nitric oxide as a charged species, i.e., nitrosonium (NO⁺) ornitroxyl (NO−), or as the neutral species, nitric oxide (NO.), and/orstimulates endogenous production of nitric oxide or EDRF in vivo and/oris a substrate for nitric oxide synthase. The kit can further compriseat least one therapeutic agent. The nitrosated and/or nitrosylated COX-2inhibitor, the nitric oxide donor and/or therapeutic agent, can beseparate components in the kit or can be in the form of a composition inone or more pharmaceutically acceptable carriers.

[0014] Yet another aspect of the present invention provides kitscomprising at least one parent COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide as a charged species,i.e., nitrosonium (NO⁺) or nitroxyl (NO−), or as the neutral species,nitric oxide (NO.), and/or stimulates endogenous production of nitricoxide or EDRF in vivo and/or is a substrate for nitric oxide synthase.The kit can further comprise at least one therapeutic agent. The parentCOX-2 inhibitor, the nitric oxide donor and/or therapeutic agent, can beseparate components in the kit or can be in the form of a composition inone or more pharmaceutically acceptable carriers.

[0015] These and other aspects of the present invention are explained indetail herein.

BRIEF DESCRIPTION OF THE FIGURES

[0016]FIG. 1 shows the relaxation of rat aortic smooth muscle rings by(a) isosorbide dinitrate (ISDN, open triangles); (b) Example 1a(non-nitrosated compound, open circles); and (c) Example 1b (nitrosatedcompound, open squares). The non-nitrosated compound of Example 1a didnot relax the tissue. At higher concentrations, the relaxation of thenitrosated compound of Example 1b was similar to that obtained withISDN. Total number of samples tested varied from a minimum of 5 to amaximum of 12. In the x axis, log M corresponds to ten fold increases ofthe test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴). Results areexpressed as the mean±standard error of the mean of the percentage oftotal relaxation induced by 10 μM phenylephrine.

[0017]FIG. 2 shows the relaxation of rat aortic smooth muscle rings by(a) isosorbide dinitrate (ISDN, open triangles); (b) Example 2a(non-nitrosated compound, open squares); and (c) Example 2b (nitrosatedcompound, open circles). The non-nitrosated compound of Example 2a didnot relax the tissue. At higher concentrations, the relaxation of thenitrosated compound of Example 2b was comparable to that obtained withISDN. Total number of samples tested varied from a minimum of 6 to amaximum of 12. In the x axis, log M corresponds to ten fold increases ofthe test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴). Results areexpressed as the mean±standard error of the mean of the percentage oftotal relaxation induced by 10 μM phenylephrine.

[0018]FIG. 3 shows the relaxation of rat aortic smooth muscle rings by(a) S-nitrosoglutathione (GSNO, open triangles); (b) Example 3e(non-nitrosylated compound, open squares); and (c) Example 3g(nitrosylated compound, open circles). The non-nitrosylated compound ofExample 3e did not relax the tissue. At higher concentrations, therelaxation of the nitrosylated compound of Example 3g was comparable tothat obtained with GSNO. Total number of samples tested varied from aminimum of 4 to a maximum of 12. In the x axis, log M corresponds to tenfold increases of the test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴).Results are expressed as the mean±standard error of the mean of thepercentage of total relaxation induced by 10 μM phenylephrine.

[0019]FIG. 4 shows the relaxation of rat aortic smooth muscle rings by(a) isosorbide dinitrate (ISDN, open circles); (b) Example 20c(non-nitrosated compound, open inverted triangles); and (c) Example 20d(nitrosated compound, open squares). The non-nitrosated compound ofExample 20c did not relax the tissue. At higher concentrations, therelaxation of the nitrosated compound of Example 20d was comparable tothat obtained with ISDN. Total number of samples tested varied from aminimum of 4 to a maximum of 16. In the x axis, log M corresponds to tenfold increases of the test compound from 100 nM (10⁻⁷) to 100 μM (10⁻⁴).Results are expressed as the mean±standard error of the mean of thepercentage of total relaxation induced by 10 μM phenylephrine.

[0020]FIG. 5 shows that anti-inflammatory effect of (a) Celecoxib (openbars); (b) Example 2a (non-nitrosated compound, horizontal strippedbars); and (c) Example 2b (nitrosated compound, hatched bars) using thecarrageenan-induced paw edema test. Total samples, 5 for eachconcentration of test compound. The x axis corresponds to the dose ofthe test compounds in μmol/kg body weight of the rats. The y axiscorresponds to the increase in the paw volume (mL). Results areexpressed as the mean±standard error of the change in paw volume. Datawas analyzed by AVONA analysis followed by Student Newmann-Keulspost-hoc test.

DETAILED DESCRIPTION OF THE INVENTION

[0021] As used throughout the disclosure, the following terms, unlessotherwise indicated, shall be understood to have the following meanings.

[0022] “NSAID” refers to a nonsteroidal anti-inflammatory compound or anonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, theenzyme responsible for the biosyntheses of the prostaglandins andcertain autocoid inhibitors, including inhibitors of the variousisozymes of cyclooxygenase (including but not limited tocyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase andlipoxygenase.

[0023] “Cyclooxygenase-2 (COX-2) inhibitor” refers to a compound thatselectively inhibits the cyclooxygenase-2 enzyme over thecyclooxygenase-1 enzyme. Preferably, the compound has a cyclooxygenase-2IC₅₀ of less than about 0.5 μM, and also has a selectivity ratio ofcyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least50, and more preferably of at least 100. Even more preferably, thecompound has a cyclooxygenase-1 IC₅₀ of greater than about 1 μM, andmore preferably of greater than 20 μM. The compound can also inhibit theenzyme, lipoxygenase and/or phosphodiestase. Such preferred selectivitymay indicate an ability to reduce the incidence of common NSAID-inducedside effects.

[0024] “Parent COX-2 inhibitor” refers to a non-nitrosated and/ornon-nitrosylated COX-2 inhibitor and includes those described in theprior art, including those described in the patents and publicationscited herein, as well as the novel compounds described herein. “ParentCOX-2 inhibitor” includes the compounds of formulas I to XVI before theyare nitrosated and/or nitrosylated by the methods described herein.

[0025] “Therapeutic agent” includes any therapeutic agent that can beused to treat or prevent the diseases described herein. “Therapeuticagents” include, for example, steroids, nonsteroidal antiinflammatorycompounds, 5-lipoxygenase inhibitors, leukotriene B₄ receptorantagonists, leukotriene A₄ hydrolase inhibitors, 5-HT agonists,3-hydroxy-3-methylglutaryl coenzyme A inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike. Although NO donors have therapeutic activity, the term“therapeutic agent” does not include the NO donors described herein,since NO donors are separately defined.

[0026] “Patient” refers to animals, preferably mammals, most preferablyhumans, and includes males and females, and children and adults.

[0027] “Therapeutically effective amount” refers to the amount of thecompound and/or composition that is effective to achieve its intendedpurpose.

[0028] “Transdermal” refers to the delivery of a compound by passagethrough the skin and into the blood stream.

[0029] “Transmucosal” refers to delivery of a compound by passage of thecompound through the mucosal tissue and into the blood stream.

[0030] “Penetration enhancement” or “permeation enhancement” refers toan increase in the permeability of the skin or mucosal tissue to aselected pharmacologically active compound such that the rate at whichthe compound permeates through the skin or mucosal tissue is increased.

[0031] “Carriers” or “vehicles” refers to carrier materials suitable forcompound administration and include any such material known in the artsuch as, for example, any liquid, gel, solvent, liquid diluent,solubilizer, or the like, which is non-toxic and which does not interactwith any components of the composition in a deleterious manner.

[0032] “Nitric oxide adduct” or “NO adduct” refers to compounds andfunctional groups which, under physiological conditions, can donate,release and/or directly or indirectly transfer any of the three redoxforms of nitrogen monoxide (NO⁺, NO⁻, NO.), such that the biologicalactivity of the nitrogen monoxide species is expressed at the intendedsite of action.

[0033] “Nitric oxide releasing” or “nitric oxide donating” refers tomethods of donating, releasing and/or directly or indirectlytransferring any of the three redox forms of nitrogen monoxide (NO⁺,NO−, NO.), such that the biological activity of the nitrogen monoxidespecies is expressed at the intended site of action.

[0034] “Nitric oxide donor” or “NO donor” refers to compounds thatdonate, release and/or directly or indirectly transfer a nitrogenmonoxide species, and/or stimulate the endogenous production of nitricoxide or endothelium-derived relaxing factor (EDRF) in vivo and/orelevate endogenous levels of nitric oxide or EDRF in vivo. “NO donor”also includes compounds that are substrates for nitric oxide synthase.

[0035] “Alkyl” refers to a lower alkyl group, a haloalkyl group, ahydroxyalkyl group, an alkenyl group, an alkynyl group, a bridgedcycloalkyl group, a cycloalkyl group or a heterocyclic ring, as definedherein. An alkyl group may also comprise one or more radical species,such as, for example a cycloalkylalkyl group or a heterocyclicalkylgroup.

[0036] “Lower alkyl” refers to a branched or straight chain acyclicalkyl group comprising one to about ten carbon atoms (preferably one toabout eight carbon atoms, more preferably one to about six carbonatoms). Exemplary lower alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl,iso-amyl, hexyl, octyl, and the like.

[0037] “Substituted lower alkyl” refers to a lower alkyl group, asdefined herein, wherein one or more of the hydrogen atoms have beenreplaced with one or more R¹⁰⁰ groups, wherein each R¹⁰⁰ isindependently a hydroxy, an oxo, a carboxyl, a carboxamido, a halo, acyano or an amino group, as defined herein.

[0038] “Haloalkyl” refers to a lower alkyl group, an alkenyl group, analkynyl group, a bridged cycloalkyl group, a cycloalkyl group or aheterocyclic ring, as defined herein, to which is appended one or morehalogens, as defined herein. Exemplary haloalkyl groups includetrifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl,and the like.

[0039] “Alkenyl” refers to a branched or straight chain C₂-C₁₀hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆hydrocarbon) which can comprise one or more carbon-carbon double bonds.Exemplary alkenyl groups include propylenyl, buten-1-yl, isobutenyl,penten-1-yl, 2,2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl,hepten-1-yl, octen-1-yl, and the like.

[0040] “Lower alkenyl” refers to a branched or straight chain C₂-C₄hydrocarbon which can comprise one or two carbon-carbon double bonds.

[0041] “Substituted alkenyl” refers to a branched or straight chainC₂-C₁₀ hydrocarbon (preferably a C₂-C₈ hydrocarbon, more preferably aC₂-C₆ hydrocarbon) which can comprise one or more carbon-carbon doublebonds, wherein one or more of the hydrogen atoms have been replaced withone or more R¹⁰⁰ groups, wherein each R¹⁰⁰ is independently a hydroxy,an oxo, a carboxyl, a carboxamido, a halo, a cyano or an amino group, asdefined herein.

[0042] “Alkynyl” refers to an unsaturated acyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds. Exemplaryalkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl,pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl,hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like.

[0043] “Bridged cycloalkyl” refers to two or more cycloalkyl groups,heterocyclic groups, or a combination thereof fused via adjacent ornon-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylicester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary bridgedcycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl,2,6-dioxabicyclo(3.3.0)octane, 7-oxabycyclo(2.2.1)heptyl,8-azabicyclo(3,2,1)oct-2-enyl and the like.

[0044] “Cycloalkyl” refers to a saturated or unsaturated cyclichydrocarbon comprising from about 3 to about 10 carbon atoms. Cycloalkylgroups can be unsubstituted or substituted with one, two or threesubstituents independently selected from alkyl, alkoxy, amino,alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl,amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid,alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo,alkylsulfinyl, and nitro. Exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,cyclohepta,1,3-dienyl, and the like.

[0045] “Heterocyclic ring or group” refers to a saturated or unsaturatedcyclic hydrocarbon group having about 2 to about 10 carbon atoms(preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbonatoms are replaced by one or more nitrogen, oxygen and/or sulfur atoms.Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state. Theheterocyclic ring or group can be fused to an aromatic hydrocarbongroup. Heterocyclic groups can be unsubstituted or substituted with one,two or three substituents independently selected from alkyl, alkoxy,amino, alkylthio, aryloxy, arylthio, arylalkyl, hydroxy, oxo, thial,halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylicester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester,alkylcarbonyl, arylcarbonyl, alkylsulfinyl, carboxamido,alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester,sulfonamido and nitro. Exemplary heterocyclic groups include pyrrolyl,3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4-dihydropyridinyl,pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl,imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl,pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, imidazolinyl,imidazolindinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl,1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl,4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl,1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, benzothiazolinyl,quinolinyl, and the like.

[0046] “Heterocyclic compounds” refer to mono- and polycyclic compoundscomprising at least one aryl or heterocyclic ring.

[0047] “Aryl” refers to a monocyclic, bicyclic, carbocyclic orheterocyclic ring system comprising one or two aromatic rings. Exemplaryaryl groups include phenyl, pyridyl, napthyl, quinoyl,tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.Aryl groups (including bicyclic aryl groups) can be unsubstituted orsubstituted with one, two or three substituents independently selectedfrom alkyl, alkoxy, alkylthio, amino, alkylamino, dialkylamino,arylamino, diarylamino, alkylarylamino, halo, cyano, alkylsulfinyl,hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid,alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester,alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido,alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamidoand nitro. Exemplary substituted aryl groups include tetrafluorophenyl,pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfonyl, and thelike.

[0048] “Cycloalkenyl” refers to an unsaturated cyclic C₂-C₁₀ hydrocarbon(preferably a C₂-C₈ hydrocarbon, more preferably a C₂-C₆ hydrocarbon)which can comprise one or more carbon-carbon triple bonds.

[0049] “Arylalkyl” refers to an aryl radical, as defined herein,attached to an alkyl radical, as defined herein. Exemplary arylalkylgroups include benzyl, phenylethyl, 4-hydroxybenzyl, 3-fluorobenzyl,2-fluorophenylethyl, and the like.

[0050] “Arylalkenyl” refers to an aryl radical, as defined herein,attached to an alkenyl radical, as defined herein. Exemplary arylalkenylgroups include styryl, propenylphenyl, and the like.

[0051] “Cycloalkylalkyl” refers to a cycloalkyl radical, as definedherein, attached to an alkyl radical, as defined herein.

[0052] “Cycloalkylalkoxy” refers to a cycloalkyl radical, as definedherein, attached to an alkoxy radical, as defined herein.

[0053] “Cycloalkylalkylthio” refers to a cycloalkyl radical, as definedherein, attached to an alkylthio radical, as defined herein.

[0054] “Heterocyclicalkyl” refers to a heterocyclic ring radical, asdefined herein, attached to an alkyl radical, as defined herein.

[0055] “Arylheterocyclic ring” refers to a bi- or tricyclic ringcomprised of an aryl ring, as defined herein, appended via two adjacentcarbon atoms of the aryl ring to a heterocyclic ring, as defined herein.Exemplary arylheterocyclic rings include dihydroindole,1,2,3,4-tetra-hydroquinoline, and the like.

[0056] “Alkoxy” refers to R₅₀O—, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group or a haloalkyl group, asdefined herein). Exemplary alkoxy groups include methoxy, ethoxy,t-butoxy, cyclopentyloxy, trifluoromethoxy, and the like.

[0057] “Aryloxy” refers to R₅₅O—, wherein R₅₅ is an aryl group, asdefined herein. Exemplary aryloxy groups include napthyloxy,quinolyloxy, isoquinolizinyloxy, and the like.

[0058] “Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, asdefined herein.

[0059] “Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as definedherein, to which is appended an aryl group, as defined herein. Exemplaryarylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy,and the like.

[0060] “Alkoxyalkyl” refers to an alkoxy group, as defined herein,appended to an alkyl group, as defined herein. Exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, isopropoxymethyl, and thelike.

[0061] “Alkoxyhaloalkyl” refers to an alkoxy group, as defined herein,appended to a haloalkyl group, as defined herein. Exemplaryalkoxyhaloalkyl groups include 4-methoxy-2-chlorobutyl and the like.

[0062] “Cycloalkoxy” refers to R₅₄O—, wherein R₅₄ is a cycloalkyl groupor a bridged cycloalkyl group, as defined herein. Exemplary cycloalkoxygroups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and thelike.

[0063] “Cycloalkylthio” refers to R₅₄S—, wherein R₅₄ is a cycloalkylgroup or a bridged cycloalkyl group, as defined herein. Exemplarycycloalkylthio groups include cyclopropylthio, cyclopentylthio,cyclohexylthio, and the like.

[0064] “Haloalkoxy” refers to an alkoxy group, as defined herein, inwhich one or more of the hydrogen atoms on the alkoxy group aresubstituted with halogens, as defined herein. Exemplary haloalkoxygroups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.

[0065] “Hydroxy” refers to —OH.

[0066] “Oxo” refers to ═O.

[0067] “Oxy” refers to —O⁻R₇₇ ⁺ wherein R₇₇ is an organic or inorganiccation.

[0068] “Organic cation” refers to a positively charged organic ion.Exemplary organic cations include alkyl substituted ammonium cations,and the like.

[0069] “Inorganic cation” refers to a positively charged metal ion.Exemplary inorganic cations include Group I metal cations such as forexample, sodium, potassium, and the like.

[0070] “Hydroxyalkyl” refers to a hydroxy group, as defined herein,appended to an alkyl group, as defined herein.

[0071] “Nitrate” refers to —O—NO₂.

[0072] “Nitrite” refers to —O—NO.

[0073] “Thionitrate” refers to —S—NO₂.

[0074] “Thionitrite” and “nitrosothiol” refer to —S—NO.

[0075] “Nitro” refers to the group —NO₂ and “nitrosated” refers tocompounds that have been substituted therewith.

[0076] “Nitroso” refers to the group —NO and “nitrosylated” refers tocompounds that have been substituted therewith.

[0077] “Nitrile” and “cyano” refer to —CN.

[0078] “Halogen” or “halo” refers to iodine (I), bromine (Br), chlorine(Cl), and/or fluorine (F).

[0079] “Amino” refers to —NH₂, an alkylamino group, a dialkylaminogroup, an arylamino group, a diarylamino group, an alkylarylamino groupor a heterocyclic ring, as defined herein.

[0080] “Alkylamino” refers to R₅₀NH—, wherein R₅₀ is an alkyl group, asdefined herein. Exemplary alkylamino groups include methylamino,ethylamino, butylamino, cyclohexylamino, and the like.

[0081] “Arylamino” refers to R₅₅NH—, wherein R₅₅ is an aryl group, asdefined herein.

[0082] “Dialkylamino” refers to R₅₂R₅₃N—, wherein R₅₂ and R₅₃ are eachindependently an alkyl group, as defined herein. Exemplary dialkylaminogroups include dimethylamino, diethylamino, methyl propargylamino, andthe like.

[0083] “Diarylamino” refers to R₅₅R₆₀N—, wherein R₅₅ and R₆₀ are eachindependently an aryl group, as defined herein.

[0084] “Alkylarylamino or arylalkylamino” refers to R₅₂R₅₅N—, whereinR₅₂ is an alkyl group, as defined herein, and R₅₅ is an aryl group, asdefined herein.

[0085] “Alkylarylalkylamino” refers to R₅₂R₇₉N—, wherein R₅₂ is an alkylgroup, as defined herein, and R₇₉ is an arylalkyl group, as definedherein.

[0086] “Alkylcycloalkylamino” refers to R₅₂R₈₀N—, wherein R₅₂ is analkyl group, as defined herein, and R₈₀ is an cycloalkyl group, asdefined herein.

[0087] “Aminoalkyl” refers to an amino group, an alkylamino group, adialkylamino group, an arylamino group, a diarylamino group, analkylarylamino group or a heterocyclic ring, as defined herein, to whichis appended an alkyl group, as defined herein. Exemplary aminoalkylgroups include dimethylaminopropyl, diphenylaminocyclopentyl,methylaminomethyl, and the like.

[0088] “Aminoaryl” refers to an aryl group to which is appended analkylamino group, a arylamino group or an arylalkylamino group.Exemplary aminoaryl groups include anilino, N-methylanilino,N-benzylanilino, and the like.

[0089] “Thio” refers to —S—.

[0090] “Sulfinyl” refers to —S(O)—.

[0091] “Methanthial” refers to —C(S)—.

[0092] “Thial” refers to ═S.

[0093] “Sulfonyl” refers to —S(O)₂ ⁻.

[0094] “Sulfonic acid” refers to —S(O)₂OR₇₆, wherein R₇₆ is a hydrogen,an organic cation or an inorganic cation, as defined herein.

[0095] “Alkylsulfonic acid” refers to a sulfonic acid group, as definedherein, appended to an alkyl group, as defined herein.

[0096] “Arylsulfonic acid” refers to an sulfonic acid group, as definedherein, appended to an aryl group, as defined herein

[0097] “Sulfonic ester” refers to —S(O)₂OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group or an aryl heterocyclic ring, as defined herein.

[0098] “Sulfonamido” refers to —S(O)₂—N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇are each independently a hydrogen atom, an alkyl group, an aryl group oran arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0099] “Alkylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an alkyl group, as defined herein.

[0100] “Arylsulfonamido” refers to a sulfonamido group, as definedherein, appended to an aryl group, as defined herein.

[0101] “Alkylthio” refers to R₅₀S—, wherein R₅₀ is an alkyl group, asdefined herein (preferably a lower alkyl group, as defined herein).

[0102] “Arylthio” refers to R₅₅S—, wherein R₅₅ is an aryl group, asdefined herein.

[0103] “Arylalkylthio” refers to an aryl group, as defined herein,appended to an alkylthio group, as defined herein.

[0104] “Alkylsulfinyl” refers to R₅₀—S(O)—, wherein R₅₀ is an alkylgroup, as defined herein.

[0105] “Alkylsulfonyl” refers to R₅₀—S(O)₂—, wherein R₅₀ is an alkylgroup, as defined herein.

[0106] “Alkylsulfonyloxy” refers to R₅₀—S(O)₂—O—, wherein R₅₀ is analkyl group, as defined herein.

[0107] “Arylsulfinyl” refers to R₅₅—S(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0108] “Arylsulfonyl” refers to R₅₅—S(O)₂—, wherein R₅₅ is an arylgroup, as defined herein.

[0109] “Arylsulfonyloxy” refers to R₅₅—S(O)₂—O—, wherein R₅₅ is an arylgroup, as defined herein.

[0110] “Amidyl” refers to R₅₁C(O)N(R₅₇)— wherein R₅₁ and R₅₇ are eachindependently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein.

[0111] “Ester” refers to R₅₁C(O)O— wherein R₅₁ is a hydrogen atom, analkyl group, an aryl group or an arylheterocyclic ring, as definedherein.

[0112] “Carbamoyl” refers to —O—C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ taken togetherare a heterocyclic ring, a cycloalkyl group or a bridged cycloalkylgroup, as defined herein.

[0113] “Carboxyl” refers to —C(O)OR₇₆, wherein R₇₆ is a hydrogen, anorganic cation or an inorganic cation, as defined herein.

[0114] “Carbonyl” refers to —C(O)—.

[0115] “Alkylcarbonyl” refers to R₅₂—C(O)—, wherein R₅₂ is an alkylgroup, as defined herein.

[0116] “Arylcarbonyl” refers to R₅₅—C(O)—, wherein R₅₅ is an aryl group,as defined herein.

[0117] “Arylalkylcarbonyl” refers to R₅₅—R₅₂—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0118] “Alkylarylcarbonyl” refers to R₅₂—R₅₅—C(O)—, wherein R₅₅ is anaryl group, as defined herein, and R₅₂ is an alkyl group, as definedherein.

[0119] “Heterocyclicalkylcarbonyl” refer to R₇₈C(O)— wherein R₇₈ is aheterocyclicalkyl group, as defined herein.

[0120] “Carboxylic ester” refers to —C(O)OR₅₈, wherein R₅₈ is an alkylgroup, an aryl group or an aryl heterocyclic ring, as defined herein.

[0121] “Alkylcarboxylic acid” and “alkylcarboxyl” refer to an alkylgroup, as defined herein, appended to a carboxyl group, as definedherein.

[0122] “Alkylcarboxylic ester” refers to an alkyl group, as definedherein, appended to a carboxylic ester group, as defined herein.

[0123] “Arylcarboxylic acid” refers to an aryl group, as defined herein,appended to a carboxyl group, as defined herein.

[0124] “Arylcarboxylic ester” and “arylcarboxyl” refer to an aryl group,as defined herein, appended to a carboxylic ester group, as definedherein.

[0125] “Carboxamido” refers to —C(O)N(R₅₁)(R₅₇), wherein R₅₁ and R₅₇ areeach independently a hydrogen atom, an alkyl group, an aryl group or anarylheterocyclic ring, as defined herein, or R₅₁ and R₅₇ when takentogether are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0126] “Alkylcarboxamido” refers to an alkyl group, as defined herein,appended to a carboxamido group, as defined herein.

[0127] “Arylcarboxamido” refers to an aryl group, as defined herein,appended to a carboxamido group, as defined herein.

[0128] “Urea” refers to —N(R₅₉)—C(O)N(R₅₁)(R₅₇) wherein R₅₁, R₅₇, andR₅₉ are each independently a hydrogen atom, an alkyl group, an arylgroup or an arylheterocyclic ring, as defined herein, or R₅₁ and R₅₇taken together are a heterocyclic ring, a cycloalkyl group or a bridgedcycloalkyl group, as defined herein.

[0129] “Phosphoryl” refers to —P(R₇₀)(R₇₁)(R₇₂), wherein R₇₀ is a lonepair of electrons, thial or oxo, and R₇₁ and R₇₂ are each independentlya covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, ahydroxy, an oxy or an aryl, as defined herein.

[0130] “Silyl” refers to —Si(R₇₃)(R₇₄)(R₇₅), wherein R₇₃, R₇₄ and R₇₅are each independently a covalent bond, a lower alkyl, an alkoxy, anaryl or an arylalkoxy, as defined herein.

[0131] Compounds that donate, transfer or release nitric oxide speciesin vivo have been recognized as having a wide spectrum of advantages andapplications. The present invention is based on the unexpected discoveryof the effects of such compounds alone and together with one or moreCOX-2 inhibitors directly or indirectly linked with one or more nitricoxide moieties. Treatment or prevention of inflammation, pain and fever;treatment and/or improvement of the gastrointestinal properties of COX-2inhibitors; facilitation of wound healing; and treatment and/orprevention of renal toxicity and cyclooxygenase-2 mediated disorders canbe obtained by the use of the nitrosated and/or nitrosylated COX-2inhibitors of the present invention; or by the use of the nitrosatedand/or nitrosylated COX-2 inhibitors in conjunction with one or morecompounds that donate, release or transfer nitric oxide and/or stimulateendogenous production of NO and/or EDRF in vivo and/or is a substratefor nitric oxide synthase, and, optionally, with one or more therapeuticagents.

[0132] In one embodiment, the present invention describes nitrosatedand/or nitrosylated COX-2 inhibitors of Formula (I):

[0133] wherein:

[0134] when side b is a double bond, and sides a and c are single bonds,—X¹—Y¹—Z¹— is:

[0135] (a) —CR⁴(R⁵)—CR⁵(R⁵′)—CR⁴(R⁵)—;

[0136] (b) —C(O)—CR⁴(R⁴′)—CR⁵(R⁵′)—;

[0137] (c) —CR⁴(R⁴′)—CR⁵(R⁵′)—C(O)—;

[0138] (d) —(CR⁵(R⁵′))_(k)—O—C(O)—;

[0139] (e) —C(O)—O—(CR⁵(R⁵′))_(k)—;

[0140] (f) —CR⁴(R⁴′)—NR³—CR⁵(R⁵′)—;

[0141] (g) —CR⁵(R⁵′)—NR³—C(O)—;

[0142] (h) —CR⁴═CR⁴′—S—;

[0143] (i) —S—CR⁴═CR⁴′—;

[0144] (j) —S—N═CR⁴—;

[0145] (k) —CR⁴═N—S—;

[0146] (l) —N═CR⁴—O—;

[0147] (m) —O—CR⁴═N—;

[0148] (n) —NR³—CR⁴═N—;

[0149] (o) —N═CR⁴—S—;

[0150] (p) —S—CR⁴═N—;

[0151] (q) —C(O)—NR³—CR⁵′(R⁵′)—;

[0152] (r) —R³N—CR⁵═CR⁵′—;

[0153] (s) —CR⁴═CR⁵—NR³—;

[0154] (t) —O—N═CR⁴—;

[0155] (u) —CR⁴═N—O—;

[0156] (v) —N═N—S—;

[0157] (w) —S—N═N—;

[0158] (x) —R³N—CR⁴═N—;

[0159] (y) —N═CR⁴—NR³—;

[0160] (z) —R³N—N═N—;

[0161] (aa) —N═N—NR³—;

[0162] (bb) —CR⁴(R^(4′))—O—CR⁵(R⁵′)—;

[0163] (cc) —CR⁴(R^(4′))—S—CR⁵(R⁵′)—;

[0164] (dd) —CR⁴(R^(4′))—C(O)—CR⁵(R⁵′)—;

[0165] (ee) —CR⁴(R^(4′))—CR⁵(R⁵′)—C(S)—;

[0166] (ff) —(CR⁵(R⁵′))_(k)—O—C(S)—;

[0167] (gg) —C(S)—O—(CR⁵(R⁵′))_(k)—;

[0168] (hh) —(CR⁵(R⁵′))_(k)—NR³—C(S)—;

[0169] (ii) —C(S)—NR³—(CR⁵(R⁵′))_(k)—;

[0170] (jj) —(CR⁵(R⁵′))_(k)—S—C(O)—;

[0171] (kk) —C(O)—S—(CR⁵(R⁵′))_(k)—;

[0172] (ll) —O—CR⁴═CR⁵—;

[0173] (mm) —CR⁴═CR⁵—O—;

[0174] (nn) —C(O)—NR³—S—;

[0175] (oo) —S—NR³—C(O)—;

[0176] (pp) —C(O)—NR³—O—;

[0177] (qq) —O—NR³—C(O)—;

[0178] (rr) —NR³—CR⁴═CR⁵—;

[0179] (ss) —CR⁴═N—NR³—;

[0180] (tt) —NR³—N═CR⁴—;

[0181] (uu) —C(O)—NR³—NR³—;

[0182] (vv) —NR³—NR³—C(O)—;

[0183] (ww) —C(O)—O—NR³—;

[0184] (xx) —NR³—O—C(O)—;

[0185] (yy) —CR⁴R⁴′—CR⁵R^(5′);

[0186] (zz) —C(O)—CR⁴R^(4′)—

[0187] (aaa) —CR⁴R^(4′)—C(O)—;

[0188] (bbb) —C(S)—CR⁴R^(4′)—;

[0189] (ccc) —CR⁴R^(4′)—C(S)—;

[0190] (ddd) —C(═NR³)—CR⁴R^(4′)—; or

[0191] (eee) —CR⁴R^(4′)—C(═NR³)—;

[0192] when sides a and c are double bonds and side b is a single bond,—X¹—Y¹—Z¹— is:

[0193] (a) ═CR⁴—O—CR⁵═;

[0194] (b) ═CR⁴—NR³—CR⁵═;

[0195] (c) ═N—S—CR⁴═;

[0196] (d) ═CR⁴—S—N═;

[0197] (e) ═N—O—CR⁴═;

[0198] (f) ═CR⁴—O—N═;

[0199] (g) ═N—S—N═;

[0200] (h) ═N—O—N═;

[0201] (i) ═N—NR³—CR⁴═;

[0202] (j) ═CR⁴—NR³—N═;

[0203] (k) ═N—NR³—N═;

[0204] (l) ═CR⁴—S—CR⁵═; or

[0205] (m) ═CR⁴—CR⁴(R^(4′))—CR⁵═;

[0206] R¹ is:

[0207] (a) —S(O)₂—CH₃;

[0208] (b) —S(O)₂—NR⁸(D¹);

[0209] (c) —S(O)₂—N(D¹)—C(O)—CF₃;

[0210] (d) —S(O)—(NH)—NH(D¹);

[0211] (e) —S(O)—(NH)—N(D¹)—C(O)—CF₃;

[0212] (f) —P(O)(CH₃)NH(D¹);

[0213] (g) —P(O)(CH₃)₂;

[0214] (h) —C(S)—NH(D¹);

[0215] (i) —S(O)(NH)CH₃;

[0216] (j) —P(O)(CH₃)OD¹; or

[0217] (k) —P(O)(CH₃)NH(D¹);

[0218] R^(1′) is:

[0219] (a) hydrogen;

[0220] (b) halogen;

[0221] (c) methyl; or

[0222] (d) CH₂OH;

[0223] R² is:

[0224] (a) lower alkyl;

[0225] (b) cycloalkyl;

[0226] (c) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

[0227] (1) hydrogen;

[0228] (2) halo;

[0229] (3) alkoxy;

[0230] (4) alkylthio;

[0231] (5) CN;

[0232] (6) haloalkyl, preferably CF₃;

[0233] (7) lower alkyl;

[0234] (8) N₃;

[0235] (9) —CO₂D¹;

[0236] (10) —CO₂-lower alkyl;

[0237] (11) —(C(R⁵)(R⁶))_(z)—OD¹;

[0238] (12) —(C(R⁵)(R⁶))_(z)—O—lower alkyl;

[0239] (13) lower alkyl-CO₂—R⁵;

[0240] (14) —OD¹;

[0241] (15) haloalkoxy;

[0242] (16) amino;

[0243] (17) nitro;

[0244] (18) alkylsulfinyl; or

[0245] (19) heteroaryl;

[0246] (d) mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:

[0247] (1) hydrogen;

[0248] (2) halo;

[0249] (3) lower alkyl;

[0250] (4) alkoxy;

[0251] (5) alkylthio;

[0252] (6) CN;

[0253] (7) haloalkyl, preferably CF₃;

[0254] (8) N₃;

[0255] (9) —C(R⁵)(R⁶)—OD¹;

[0256] (10) —C(R⁵)(R⁶)—O-lower alkyl; or

[0257] (11) alkylsulfinyl;

[0258] (e) benzoheteroaryl which includes the benzo fused analogs of(d);

[0259] (f) —NR¹⁰R¹¹;

[0260] (g) —SR¹¹;

[0261] (h) —OR¹¹;

[0262] (i) —R¹¹;

[0263] (j) alkenyl;

[0264] (k) alkynyl;

[0265] (l) unsubstituted, mono-, di-, tri- or tetra-substitutedcycloalkenyl, wherein the substituents are each independently:

[0266] (1) halo;

[0267] (2) alkoxy;

[0268] (3) alkylthio;

[0269] (4) CN;

[0270] (5) haloalkyl, preferably CF₃;

[0271] (6) lower alkyl;

[0272] (7) N₃;

[0273] (8) —CO₂D¹;

[0274] (9) —CO₂-lower alkyl;

[0275] (10) —C(R¹²)(R¹³)—OD¹;

[0276] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0277] (12) lower alkyl-CO₂—R¹²;

[0278] (13) benzyloxy;

[0279] (14) —O-(lower alkyl)-CO₂R¹²;

[0280] (15) —O-(lower alkyl)-NR¹²R¹³; or

[0281] (16) alkylsulfinyl;

[0282] (m) mono-, di-, tri- or tetra-substituted heterocycloalkyl groupof 5, 6 or 7 members, or a benzoheterocycle, wherein saidheterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatomsselected from O, S, or N and, optionally, contains a carbonyl group or asulfonyl group, and wherein said substituents are each independently:

[0283] (1) halo;

[0284] (2) lower alkyl;

[0285] (3) alkoxy;

[0286] (4) alkylthio;

[0287] (5) CN;

[0288] (6) haloalkyl, preferably CF₃;

[0289] (7) N₃;

[0290] (8) —C(R¹²)(R¹³)—OD¹;

[0291] (9) —C(R¹²)(R¹³)—O-lower alkyl; or

[0292] (10) alkylsulfinyl;

[0293] (n) styryl, mono or di-substituted styryl, wherein thesubstituent are each independently:

[0294] (1) halo;

[0295] (2) alkoxy;

[0296] (3) alkylthio;

[0297] (4) CN;

[0298] (5) haloalkyl, preferably CF₃;

[0299] (6) lower alkyl;

[0300] (7) N₃;

[0301] (8) —CO₂D¹;

[0302] (9) —CO₂-lower alkyl;

[0303] (10) —C(R¹²)(R¹³)—OD¹;

[0304] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0305] (12) lower alkyl-CO₂—R¹²;

[0306] (13) benzyloxy;

[0307] (14) —O-(lower alkyl)-CO₂R¹²; or

[0308] (15) —O-(lower alkyl)-NR¹²R¹³;

[0309] (o) phenylacetylene, mono- or di-substituted phenylacetylene,wherein the substituents are each independently:

[0310] (1) halo;

[0311] (2) alkoxy;

[0312] (3) alkylthio;

[0313] (4) CN;

[0314] (5) haloalkyl, preferably CF₃;

[0315] (6) lower alkyl;

[0316] (7) N₃;

[0317] (8) —CO₂D¹;

[0318] (9) —CO₂-lower alkyl;

[0319] (10) —C(R¹²)(R¹³)—OD¹;

[0320] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0321] (12) lower alkyl-CO₂—R¹²;

[0322] (13) benzyloxy;

[0323] (14) —O-(lower alkyl)-CO₂R¹²; or

[0324] (15) —O-(lower alkyl)-NR¹²R¹³;

[0325] (p) fluoroalkenyl;

[0326] (q) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10members, containing 2, 3, 4 or 5 heteroatoms, wherein at least oneheteroatom resides on each ring of said bicyclic heteroaryl, saidheteroatoms are each independently O, S and N and said substituents areeach independently:

[0327] (1) hydrogen;

[0328] (2) halo;

[0329] (3) lower alkyl;

[0330] (4) alkoxy;

[0331] (5) alkylthio;

[0332] (6) CN;

[0333] (7) haloalkyl, preferably CF₃;

[0334] (8) N₃;

[0335] (9) —C(R⁵)(R⁶)—OD¹; or

[0336] (10) —C(R⁵)(R⁶)—O-lower alkyl;

[0337] (r) K;

[0338] (s) aryl;

[0339] (t) arylalkyl;

[0340] (u) cycloalkylalkyl;

[0341] (v) —C(O)R¹¹;

[0342] (u) hydrogen;

[0343] (v) arylalkenyl;

[0344] (w) arylalkoxy;

[0345] (x) alkoxy;

[0346] (y) aryloxy;

[0347] (z) cycloalkoxy;

[0348] (aa) arylthio;

[0349] (bb) alkylthio;

[0350] (cc) arylalkylthio; or

[0351] (dd) cycloalkylthio;

[0352] R³ is:

[0353] (a) hydrogen;

[0354] (b) haloalkyl, preferably CF₃;

[0355] (c) CN;

[0356] (d) lower alkyl;

[0357] (e) —(C(R_(e))(R_(f)))_(p)—U—V;

[0358] (f) K;

[0359] (g) unsubstituted or substituted:

[0360] (1) lower alkyl-Q;

[0361] (2) lower alkyl-O-lower alkyl-Q;

[0362] (3) lower alkyl-S-lower alkyl-Q;

[0363] (4) lower alkyl-O—Q;

[0364] (5) lower alkyl-S—Q;

[0365] (6) lower alkyl-O—V;

[0366] (7) lower alkyl-S—V;

[0367] (8) lower alkyl-O—K; or

[0368] (9) lower alkyl-S—K;

[0369] wherein the substituent(s) reside on the lower alkyl group;

[0370] (h) Q;

[0371] (i) alkylcarbonyl;

[0372] (j) arylcarbonyl;

[0373] (k) alkylarylcarbonyl;

[0374] (l) arylalkylcarbonyl;

[0375] (m) carboxylic ester;

[0376] (n) carboxamido;

[0377] (o) cycloalkyl;

[0378] (p) mono-, di- or tri-substituted phenyl or naphthyl, wherein thesubstituents are each independently:

[0379] (1) hydrogen;

[0380] (2) halo;

[0381] (3) alkoxy;

[0382] (4) alkylthio;

[0383] (5) CN;

[0384] (6) haloalkyl, preferably CF₃;

[0385] (7) lower alkyl;

[0386] (8) N₃;

[0387] (9) —CO₂D¹;

[0388] (10) —CO₂-lower alkyl;

[0389] (11) —(C(R⁵)(R⁶))_(z)—OD¹;

[0390] (12) —(C(R⁵)(R⁶))_(z)—O-lower alkyl;

[0391] (13) lower alkyl-CO₂—R⁵;

[0392] (14) —OD¹;

[0393] (15) haloalkoxy;

[0394] (16) amino;

[0395] (17) nitro; or

[0396] (18) alkylsulfinyl;

[0397] (q) alkenyl;

[0398] (r) alkynyl;

[0399] (s) arylalkyl;

[0400] (t) lower alkyl-OD¹;

[0401] (u) alkoxyalkyl;

[0402] (v) aminoalkyl;

[0403] (w) lower alkyl-CO₂R¹⁰;

[0404] (x) lower alkyl-C(O)NR¹⁰(R^(10′));

[0405] (y) heterocyclicalkyl; or

[0406] (z) heterocyclic ring-C(O)—;

[0407] R⁴, R⁴′, R⁵ and R⁵′ are each independently:

[0408] (a) hydrogen;

[0409] (b) amino;

[0410] (c) CN;

[0411] (d) lower alkyl;

[0412] (e) haloalkyl;

[0413] (f) alkoxy;

[0414] (g) alkylthio;

[0415] (h) Q;

[0416] (i) 13 O—Q;

[0417] (j) —S—Q;

[0418] (k) K;

[0419] (l) cycloalkoxy;

[0420] (m) cycloalkylthio;

[0421] (n) unsubstituted, mono-, or di-substituted phenyl orunsubstituted, mono-, or di-substituted benzyl, wherein the substituentsare each independently:

[0422] (1) halo;

[0423] (2) lower alkyl;

[0424] (3) alkoxy;

[0425] (4) alkylthio;

[0426] (5) CN;

[0427] (6) haloalkyl, preferably CF₃;

[0428] (7) N₃;

[0429] (8) Q;

[0430] (9) nitro; or

[0431] (10) amino;

[0432] (o) unsubstituted, mono-, or di-substituted heteroaryl orunsubstituted, mono-, or di-substituted heteroarylmethyl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; said substituents are each independently:

[0433] (1) halo;

[0434] (2) lower alkyl;

[0435] (3) alkoxy;

[0436] (4) alkylthio;

[0437] (5) CN;

[0438] (6) haloalkyl, preferably CF₃;

[0439] (7) N₃;

[0440] (8) —C(R⁶)(R⁷)—OD¹;

[0441] (9) —C(R⁶)(R⁷)—O-lower alkyl; or

[0442] (10) alkylsulfinyl

[0443] (p) —CON(R⁸)(R⁸);

[0444] (q) —CH₂OR⁸;

[0445] (r) —CH₂OCN;

[0446] (s) unsubstituted or substituted:

[0447] (1) lower alkyl-Q;

[0448] (2) —O-lower alkyl-Q;

[0449] (3) —S-lower alkyl-Q;

[0450] (4) lower alkyl-O-lower alkyl-Q;

[0451] (5) lower alkyl-S-lower alkyl-Q;

[0452] (6) lower alkyl-O—Q;

[0453] (7) lower alkyl-S—Q;

[0454] (8) lower alkyl-O—K;

[0455] (9) lower alkyl-S—K;

[0456] (10) lower alkyl-O—V; or

[0457] (11) lower alkyl-S—V;

[0458] wherein the substituent(s) resides on the lower alkyl;

[0459] (t) cycloalkyl;

[0460] (u) aryl;

[0461] (v) arylalkyl;

[0462] (w) cycloalkylalkyl;

[0463] (x) aryloxy;

[0464] (y) arylalkoxy;

[0465] (z) arylalkylthio;

[0466] (aa) cycloalkylalkoxy;

[0467] (bb) heterocycloalkyl;

[0468] (cc) alkylsulfonyloxy;

[0469] (dd) alkylsulfonyl;

[0470] (ee) arylsulfonyl;

[0471] (ff) arylsulfonyloxy;

[0472] (gg) —C(O)R¹⁰;

[0473] (hh) nitro;

[0474] (ii) amino;

[0475] (jj) aminoalkyl;

[0476] (kk) —C(O)-alkyl-heterocyclic ring;

[0477] (ll) halo;

[0478] (mm) heterocyclic ring;

[0479] (nn) —CO₂D¹;

[0480] (oo) carboxyl;

[0481] (pp) amidyl; or

[0482] (qq) alkoxyalkyl;

[0483] alternatively, R⁴ and R⁵ together with the carbons to which theyare attached are:

[0484] (a) cycloalkyl;

[0485] (b) aryl; or

[0486] (c) heterocyclic ring;

[0487] alternatively, R⁴ and R^(4′) or R⁵ and R^(5′) taken together withthe carbon to which they are attached are:

[0488] (a) cycloalkyl; or

[0489] (b) heterocyclic ring;

[0490] alternatively, R⁴ and R⁵, R^(4′) and R^(5′), R⁴ and R^(5′), orR^(4′) and R⁵ when substituents on adjacent carbon atoms taken togetherwith the carbons to which they are attached are:

[0491] (a) cycloalkyl;

[0492] (b) heterocyclic ring; or

[0493] (c) aryl;

[0494] R⁶ and R⁷ are each independently:

[0495] (a) hydrogen;

[0496] (b) unsubstituted, mono- or di-substituted phenyl; unsubstituted,mono- or di-substituted benzyl; unsubstituted, mono- or di-substitutedheteroaryl; mono- or di-substituted heteroarylmethyl, wherein saidsubstituents are each independently:

[0497] (1) halo;

[0498] (2) lower alkyl;

[0499] (3) alkoxy;

[0500] (4) alkylthio;

[0501] (5) CN;

[0502] (6) haloalkyl, preferably CF₃;

[0503] (7) N₃;

[0504] (8) —C(R¹⁴)(R¹⁵)—OD¹; or

[0505] (9) —C(R¹⁴)(R¹⁵)—O-lower alkyl;

[0506] (c) lower alkyl;

[0507] (d) —CH₂OR⁸;

[0508] (e) CN;

[0509] (f) —CH₂CN;

[0510] (g) haloalkyl, preferably fluoroalkyl;

[0511] (h) —CON(R⁸)(R⁸);

[0512] (i) halo; or

[0513] (j) —OR⁸;

[0514] R⁸ is:

[0515] (a) hydrogen;

[0516] (b) K; or

[0517] (c) R⁹;

[0518] alternatively, R⁵ and R^(5′), R⁶ and R⁷ or R⁷ and R⁸ togetherwith the carbon to which they are attached form a saturated monocyclicring of 3, 4, 5, 6 or 7 atoms; optionally containing up to twoheteroatoms selected from oxygen, S(O)_(o) or NR_(i);

[0519] R⁹ is:

[0520] (a) lower alkyl;

[0521] (b) lower alkyl-CO₂D¹;

[0522] (c) lower alkyl-NHD¹;

[0523] (d) phenyl or mono-, di- or tri-substituted phenyl, wherein thesubstituents are each independently:

[0524] (1) halo;

[0525] (2) lower alkyl;

[0526] (3) alkoxy;

[0527] (4) alkylthio;

[0528] (5) lower alkyl-CO₂D¹;

[0529] (6) lower alkyl-NHD¹;

[0530] (7) CN;

[0531] (8) CO₂D¹; or

[0532] (9) haloalkyl, preferably fluoroalkyl;

[0533] (e) benzyl, mono-, di- or tri-substituted benzyl, wherein thesubstituents are each independently:

[0534] (1) halo;

[0535] (2) lower alkyl;

[0536] (3) alkoxy;

[0537] (4) alkylthio;

[0538] (5) lower alkyl-CO₂D¹;

[0539] (6) lower alkyl-NHD¹;

[0540] (7) CN;

[0541] (8) —CO₂D¹; or

[0542] (9) haloalkyl, preferably CF₃;

[0543] (f) cycloalkyl;

[0544] (g) K; or

[0545] (h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein thesubstituents are each independently:

[0546] (1) halo;

[0547] (2) lower alkyl;

[0548] (3) alkoxy;

[0549] (4) alkylthio;

[0550] (5) lower alkyl-CO₂D¹;

[0551] (6) lower alkyl-NHD¹;

[0552] (7) CN;

[0553] (8) —CO₂D¹; or

[0554] (9) haloalkyl, preferably CF₃;

[0555] R¹⁰ and R¹⁰′ are each independently:

[0556] (a) hydrogen; or

[0557] (b) R¹¹;

[0558] R¹¹ is:

[0559] (a) lower alkyl;

[0560] (b) cycloalkyl;

[0561] (c) unsubstituted, mono-, di- or tri-substituted phenyl ornaphthyl, wherein the substituents are each independently:

[0562] (1) halo;

[0563] (2) alkoxy;

[0564] (3) alkylthio;

[0565] (4) CN;

[0566] (5) haloalkyl, preferably CF₃;

[0567] (6) lower alkyl;

[0568] (7) N₃;

[0569] (8) —CO₂D¹;

[0570] (9) —CO₂-lower alkyl;

[0571] (10) —C(R¹²)(R¹³)—OD¹;

[0572] (11) —C(R¹²)(R¹³)—O-lower alkyl;

[0573] (12) lower alkyl-CO₂D¹;

[0574] (13) lower alkyl-CO₂R¹²;

[0575] (14) benzyloxy;

[0576] (15) —O-(lower alkyl)-CO₂D¹;

[0577] (16) —O-(lower alkyl)-CO₂R¹²; or

[0578] (17) —O-(lower alkyl)-NR¹²R¹³;

[0579] (d) unsubstituted, mono-, di- or tri-substituted heteroaryl,wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, saidring having one heteroatom which is S, O, or N, and, optionally, 1, 2,or 3 additional N atoms; or said heteroaryl is a monocyclic ring of 6atoms, said ring having one heteroatom which is N, and, optionally 1, 2,or 3 additional N atoms, and wherein said substituents are eachindependently:

[0580] (1) halo;

[0581] (2) lower alkyl;

[0582] (3) alkoxy;

[0583] (4) alkylthio;

[0584] (5) CN;

[0585] (6) haloalkyl, preferably CF₃;

[0586] (7) N₃;

[0587] (8) —C(R¹²)(R¹³)—OD¹; or

[0588] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0589] (e) unsubstituted, mono- or di-substituted benzoheterocycle,wherein the benzoheterocycle is a 5, 6, or 7-membered ring whichcontains 1 or 2 heteroatoms independently selected from O, S, or N, and,optionally, a carbonyl group or a sulfonyl group, wherein saidsubstituents are each independently:

[0590] (1) halo;

[0591] (2) lower alkyl;

[0592] (3) alkoxy;

[0593] (4) alkylthio;

[0594] (5) CN;

[0595] (6) haloalkyl, preferably CF₃;

[0596] (7) N₃;

[0597] (8) —C(R¹²)(R¹³)—OD¹; or

[0598] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0599] (f) unsubstituted, mono- or di-substituted benzocarbocycle,wherein the carbocycle is a 5, 6, or 7-membered ring which optionallycontains a carbonyl group, wherein said substituents are eachindependently:

[0600] (1) halo;

[0601] (2) lower alkyl;

[0602] (3) alkoxy;

[0603] (4) alkylthio;

[0604] (5) CN;

[0605] (6) haloalkyl, preferably CF₃;

[0606] (7) N₃;

[0607] (8) —C(R¹²)(R¹³)—OD¹; or

[0608] (9) —C(R¹²)(R¹³)—O-lower alkyl;

[0609] (g) hydrogen; or

[0610] (h) K

[0611] R¹² and R¹³ are each independently:

[0612] (a) hydrogen;

[0613] (b) lower alkyl; or

[0614] (c) aryl; or

[0615] R¹² and R¹³ together with the atom to which they are attachedform a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;

[0616] R¹⁴ and R¹⁵ are each independently:

[0617] (a) hydrogen; or

[0618] (b) lower alkyl; or

[0619] R¹⁴ and R¹⁵ together with the atom to which they are attachedform a carbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6or 7 atoms;

[0620] D¹ is:

[0621] (a) hydrogen or

[0622] (b) D;

[0623] D is:

[0624] (a) V; or

[0625] (b) K;

[0626] U is:

[0627] (a) oxygen;

[0628] (b) sulfur; or

[0629] (c) —N(R_(a))(R_(l))—;

[0630] V is:

[0631] (a) —NO;

[0632] (b) —NO₂; or

[0633] (c) hydrogen

[0634] K is—W_(aa)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—U—V;wherein aa, b, c, d, g, i and j are each independently an integer from 0to 3;

[0635] p, x, y and z are each independently an integer from 0 to 10;

[0636] W at each occurrence is independently:

[0637] (a) —C(O)—;

[0638] (b) —C(S)—;

[0639] (c) —T—;

[0640] (d) —(C(R_(e))(R_(f)))_(h)—;

[0641] (e) alkyl;

[0642] (f) aryl;

[0643] (g) heterocyclic ring;

[0644] (h) arylheterocyclic ring, or

[0645] (i) —(CH₂CH₂O)_(q)—;

[0646] E at each occurrence is independently:

[0647] (a) —T—;

[0648] (b) alkyl;

[0649] (c) aryl;

[0650] (d) —(C(R_(e))(R_(f)))_(h)—;

[0651] (e) heterocyclic ring;

[0652] (f) arylheterocyclic ring; or

[0653] (g) —(CH₂CH₂O)_(q)—;

[0654] h is an integer form 1 to 10;

[0655] q is an integer from 1 to 5;

[0656] R_(e) and R_(f) are each independently:

[0657] (a) hydrogen;

[0658] (b) alkyl;

[0659] (c) cycloalkoxy;

[0660] (d) halogen;

[0661] (e) hydroxy;

[0662] (f) hydroxyalkyl;

[0663] (g) alkoxyalkyl;

[0664] (h) arylheterocyclic ring;

[0665] (i) cycloalkylalkyl;

[0666] (j) heterocyclicalkyl;

[0667] (k) alkoxy;

[0668] (l) haloalkoxy;

[0669] (m) amino;

[0670] (n) alkylamino;

[0671] (o) dialkylamino;

[0672] (p) arylamino;

[0673] (q) diarylamino;

[0674] (r) alkylarylamino;

[0675] (s) alkoxyhaloalkyl;

[0676] (t) haloalkoxy;

[0677] (u) sulfonic acid;

[0678] (v) alkylsulfonic acid;

[0679] (w) arylsulfonic acid;

[0680] (x) arylalkoxy;

[0681] (y) alkylthio;

[0682] (z) arylthio;

[0683] (aa) cyano;

[0684] (bb) aminoalkyl;

[0685] (cc) aminoaryl;

[0686] (dd) alkoxy;

[0687] (ee) aryl;

[0688] (ff) arylalkyl;

[0689] (gg) carboxamido;

[0690] (hh) alkylcarboxamido;

[0691] (ii) arylcarboxamido;

[0692] (jj) amidyl;

[0693] (kk) carboxyl;

[0694] (ll) carbamoyl;

[0695] (mm) alkylcarboxylic acid;

[0696] (nn) arylcarboxylic acid;

[0697] (oo) alkylcarbonyl;

[0698] (pp) arylcarbonyl;

[0699] (qq) ester;

[0700] (rr) carboxylic ester;

[0701] (ss) alkylcarboxylic ester;

[0702] (tt) arylcarboxylic ester;

[0703] (uu) haloalkoxy;

[0704] (vv) sulfonamido;

[0705] (ww) alkylsulfonamido;

[0706] (xx) arylsulfonamido;

[0707] (yy) alkylsulfonyl,

[0708] (zz) alkylsulfonyloxy,

[0709] (aaa) arylsulfonyl,

[0710] (bbb) arylsulphonyloxy

[0711] (ccc) sulfonic ester;

[0712] (ddd) carbamoyl;

[0713] (eee) urea;

[0714] (fff) nitro; or

[0715] (ggg) —U—V; or

[0716] R_(e) and R_(f) taken together are:

[0717] (a) oxo;

[0718] (b) thial; or

[0719] R_(e) and R_(f) taken together with the carbon to which they areattached are:

[0720] (a) heterocyclic ring;

[0721] (b) cycloalkyl group; or

[0722] (c) bridged cycloalkyl group;

[0723] k is an integer from 1 to 2;

[0724] T at each occurrence is independently:

[0725] (a) a covalent bond,

[0726] (b) carbonyl,

[0727] (c) an oxygen,

[0728] (d) —S(O)_(o)—; or

[0729] (e) —N(R_(a))(R_(l))—;

[0730] o is an integer from 0 to 2;

[0731] Q is:

[0732] (a) —C(O)—U—D¹;

[0733] (b) —CO₂-lower alkyl;

[0734] (c) tetrazolyl-5-yl;

[0735] (d) —C(R⁷)(R⁸)(S—D¹);

[0736] (e) —C(R⁷)(R⁸)(O—D¹); or

[0737] (f) —C(R⁷)(R⁸)(O-lower alkyl);

[0738] R_(a) is:

[0739] (a) a lone pair of electron;

[0740] (b) hydrogen; or

[0741] (c) lower alkyl;

[0742] R_(i) is:

[0743] (a) hydrogen;

[0744] (b) alkyl;

[0745] (c) aryl;

[0746] (d) alkylcarboxylic acid;

[0747] (e) arylcarboxylic acid;

[0748] (f) alkylcarboxylic ester;

[0749] (g) arylcarboxylic ester;

[0750] (h) alkylcarboxamido;

[0751] (i) arylcarboxamido;

[0752] (j) alkylsulfinyl;

[0753] (k) alkylsulfonyl;

[0754] (l) alkylsulfonyloxy,

[0755] (m) arylsulfinyl;

[0756] (n) arylsulfonyl;

[0757] (o) arylsulphonyloxy;

[0758] (p) sulfonamido;

[0759] (q) carboxamido;

[0760] (r) carboxylic ester;

[0761] (s) aminoalkyl;

[0762] (t) aminoaryl;

[0763] (u) —CH₂—C(U—V)(R_(e))(R_(f));

[0764] (v) a bond to an adjacent atom creating a double bond to thatatom; or

[0765] (w) —(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic or inorganic cation;

[0766] with the proviso that the compounds of Formula I must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[0767] In cases where R_(e) and R_(f) are a heterocyclic ring or R_(e)and R_(f) taken together with the carbon atoms to which they areattached are a heterocyclic ring, then R_(i) can be a substituent on anydisubstituted nitrogen contained within the radical where R_(i) is asdefined herein.

[0768] In cases where multiple designations of variables which reside insequence are chosen as a “covalent bond” or the integer chosen is 0, theintent is to denote a single covalent bond connecting one radical toanother. For example, E₀ would denote a covalent bond, while E₂ denotes(E—E) and (C(R_(e))(R_(f)))₂ denotes —C(R_(e))(R_(f))—C(R_(e))(R_(f))—.

[0769] Another embodiment of the present invention provides compounds ofthe Formula (II):

[0770] wherein:

[0771] A—B is:

[0772] (a) N—C;

[0773] (b) C—N; or

[0774] (c) N—N;

[0775] when sides d and f are double bonds, and sides e and g are singlebonds, —X²—Y²—Z²— is:

[0776] (a) ═CR⁴—CR⁴′═CR⁵—;

[0777] (b) ═N—CR⁴═CR⁴′—;

[0778] (c) ═N—CR⁴═N—;

[0779] (d) ═CR⁴—N═CR⁴′—;

[0780] (e) ═CR⁴—N═N—;

[0781] (f) ═N—N═CR⁴—;

[0782] (g) ═N—N═N—;

[0783] (h) ═CR⁴—CR⁵═N—; or

[0784] (i) ═CR^(2′)—CR⁵═N—;

[0785] R² and R^(2′) taken together are:

[0786] or R^(2′) and R⁵ taken together with the carbon atoms to whichthey are attached are:

[0787] (a) cycloalkyl; or

[0788] (b) heterocyclic ring;

[0789] R⁹⁷ is:

[0790] (a) hydrogen;

[0791] (b) alkylthio;

[0792] (c) alkylsulfinyl;

[0793] (d) alkylsulfonyl;

[0794] (e) cyano;

[0795] (f) carboxyl;

[0796] (g) amino;

[0797] (h) lower alkyl;

[0798] (i) haloalkyl;

[0799] (j) hydroxy;

[0800] (k) alkoxy;

[0801] (l) haloalkoxy;

[0802] (m) alkylarylalkylamino;

[0803] (n) aminoalkyl;

[0804] (o) aminoaryl;

[0805] (p) sulfonamido;

[0806] (q) alkylsulfonamido;

[0807] (r) arylsulfonamido;

[0808] (s) heterocyclic ring;

[0809] (t) hydroxyalkyl; or

[0810] (u) nitro;

[0811] a is an integer from 1 to 3;

[0812] when sides e and g are double bonds, and sides d andf are singlebonds, —X²—Y²—Z²— is:

[0813] (a) —CR⁴═N—N═;

[0814] (b) —N═N—CR⁴═;

[0815] (c) —CR⁴═N—CR⁴′═;

[0816] (d) —N═CR⁴—N═;

[0817] (e) —CR⁴═CR⁴′—N ═;

[0818] (f) —N═CR⁴—CR⁵═;

[0819] (g) —CR⁴═CR⁵—CR^(5′)═; or

[0820] (h) —N═N—N═;

[0821] when side g is a double bond, and sides d, e and f are singlebonds, —X²—Y²—Z²— is:

[0822] (a) —C(O)—O—CR⁴═;

[0823] (b) —C(O)—NR³—CR⁴═;

[0824] (c) —C(O)—S—CR⁴═; or

[0825] (d) —C(H)R⁴—C(OH)R⁵—N═;

[0826] when sides d is a double bond, and sides e, f and g are singlebonds, —X²—Y²—Z²— is:

[0827] (a) ═CR⁴—O—C(O)—;

[0828] (b) ═CR⁴—NR³—C(O)—;

[0829] (c) ═CR⁴—S—C(O)—; or

[0830] (d) ═N—C(OH)R⁴—C(H)R⁵—;

[0831] when sides f is a double bond, and sides d, e and g are singlebonds, —X²—Y²—Z²— is:

[0832] (a) —CH(R⁴)—CR⁵═N—; or

[0833] (b) —C(O)—CR⁴═CR⁵—;

[0834] when sides e is a double bond, and sides d, f and g are singlebonds, —X²—Y²—Z²— is:

[0835] (a) —N═CR⁴—CH(R⁵)—; or

[0836] (b) —CR⁴═CR⁵—C(O)—;

[0837] when sides d, e, f and g are single bonds, —X²—Y²—Z²— is:

[0838] (a) —C(O)—CR⁴(R^(4′))—C(O)—;

[0839] R¹, R^(1′), R², R³, R⁴, R⁴′, R⁵ and R⁵′ are as defined herein;

[0840] with the proviso that the compounds of Formula II must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[0841] Another embodiment of the present invention provides compounds ofthe Formula (III):

[0842] wherein:

[0843] X³ is:

[0844] (a) —C(O)—U—D¹;

[0845] (b) —CH₂—U—D¹;

[0846] (c) —CH₂—C(O)—CH₃;

[0847] (d) —CH₂—CH₂—C(O)—U—D¹;

[0848] (e) —CH₂—O—D¹; or

[0849] (f) —C(O)H

[0850] Y³ is:

[0851] (a) —(CR⁵(R⁵′))_(k)—U—D¹;

[0852] (b) —CH₃;

[0853] (c) —CH₂OC(O)R⁶; or (d) —C(O)H;

[0854] alternatively, X³ and Y³ taken together are—CR⁸²(R⁸³)—CR^(82′)(R^(83′))—;

[0855] R⁸², R^(82′), R⁸³ and R^(83′) are each independently:

[0856] (a) hydrogen;

[0857] (b) hydroxy;

[0858] (c) alkyl;

[0859] (d) alkoxy;

[0860] (e) lower alkyl-OD¹;

[0861] (f) alkylthio;

[0862] (g) CN;

[0863] (h) —C(O)R⁸⁴; or

[0864] (i) —OC(O)R⁸⁵;

[0865] R⁸⁴ is:

[0866] (a) hydrogen;

[0867] (b) lower alkyl; or

[0868] (c) alkoxy;

[0869] R⁸⁵ is:

[0870] (a) lower alkyl;

[0871] (b) alkoxy

[0872] (c) unsubstituted, mono-, di- or tri-substituted phenyl orpyridyl, wherein the substituents are each independently:

[0873] (1) halo;

[0874] (2) alkoxy;

[0875] (3) haloalkyl;

[0876] (4) CN;

[0877] (5) —C(O)R⁸⁴;

[0878] (6) lower alkyl;

[0879] (7) —S(O)O-lower alkyl; or

[0880] (8) —OD¹;

[0881] alternatively, R⁸² and R⁸³ or R^(82′) and R^(83′) taken togetherare:

[0882] (a) oxo;

[0883] (b) thial;

[0884] (c) ═CR⁸⁶R⁸⁷; or

[0885] (d) ═NR⁸⁸;

[0886] R⁸⁶ and R⁸⁷ are each independently:

[0887] (a) hydrogen;

[0888] (b) lower alkyl;

[0889] (c) lower alkyl-OD¹;

[0890] (d) CN; or

[0891] (e) —C(O)R⁸⁴;

[0892] R⁸⁸ is:

[0893] (a) OD¹;

[0894] (b) alkoxy;

[0895] (c) lower alkyl or

[0896] (d) unsubstituted, mono-, di- or tri-substituted phenyl orpyridyl, wherein the substituents are each independently:

[0897] (1) halo;

[0898] (2) alkoxy;

[0899] (3) haloalkyl;

[0900] (4) CN;

[0901] (5) —C(O)R⁸⁴;

[0902] (6) lower alkyl;

[0903] (7) —S(O)_(o)-lower alkyl; or

[0904] (8) —OD¹;

[0905] R¹, R², R⁵, R⁵′, R⁶, U, D¹, o and k are as defined herein;

[0906] with the proviso that the compounds of Formula III must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[0907] Another embodiment of the present invention provides compounds ofthe Formula (IV)

[0908] wherein:

[0909] X⁴ and Z⁴ are each independently:

[0910] (a) N; or

[0911] (b) CR²¹;

[0912] R²⁰ is:

[0913] (a) —S(O)₂—CH₃;

[0914] (b) —S(O)₂—NR⁸(D¹); or

[0915] (c) —S(O)₂—N(D¹)—C(O)—CF₃;

[0916] R²¹ and R²¹′ are each independently:

[0917] (a) hydrogen;

[0918] (b) lower alkyl;

[0919] (c) alkoxy;

[0920] (d) alkylthio;

[0921] (e) haloalkyl, preferably fluoroalkyl;

[0922] (f) haloalkoxy, preferably fluoroalkoxy;

[0923] (g) CN;

[0924] (h) —CO₂D¹;

[0925] (i) —CO₂R¹⁴;

[0926] (j) lower alkyl-O—D¹;

[0927] (k) lower alkyl—CO₂D¹;

[0928] (l) lower alkyl—CO₂R¹⁴;

[0929] (m) halo;

[0930] (n) —O—D¹;

[0931] (o) —N₃;

[0932] (p) —NO₂;

[0933] (q) —NR¹⁴D¹;

[0934] (r) —N(D¹)C(O)R¹⁴;

[0935] (s) —NHK;

[0936] (t) aryl;

[0937] (u) arylalkylthio;

[0938] (v) arylalkoxy;

[0939] (w) alkylamino;

[0940] (x) aryloxy;

[0941] (y) alkylarylalkylamino;

[0942] (z) cycloalkylalkylamino; or

[0943] (aa) cycloalkylalkoxy;

[0944] R²² is:

[0945] (a) mono-, di- or tri-substituted phenyl or pyridinyl (or theN-oxide thereof), wherein the substituent are each independently:

[0946] (1) hydrogen;

[0947] +P3

[0948] (2) halo;

[0949] (3) alkoxy;

[0950] (4) alkylthio;

[0951] (5) CN;

[0952] (6) lower alkyl;

[0953] (7) haloalkyl, preferably fluoroalkyl;

[0954] (8) N₃;

[0955] (9) —CO₂D¹;

[0956] (10) —CO₂-lower alkyl;

[0957] (11) —C(R¹⁴)(R¹⁵)—OD¹;

[0958] (12) —OD¹;

[0959] (13) lower alkyl-CO₂—R¹⁴; or

[0960] (14) lower alkyl-CO₂—D¹;

[0961] (b) —T—C(R²³)(R²⁴)—(C(R²⁵)(R²⁶))_(o)—C(R²⁷)(R²⁸)—U—D¹;

[0962] (c)

[0963]  (d) arylalkyl; or

[0964] (e) cycloalkylalkyl;

[0965] wherein:

[0966] R¹⁴ and R¹⁵ are each independently:

[0967] (a) hydrogen; or

[0968] (b) lower alkyl;

[0969] R²³, R²⁴, R²⁵, R²⁶, R²⁷R²⁸ are each independently:

[0970] (a) hydrogen; or

[0971] (b) lower alkyl; or

[0972] R²³ and R²⁷, or R²⁷ and R²⁸ together with the atoms to which theyare attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R²³and R²⁵ are joined to form a covalent bond;

[0973] Y⁵ is:

[0974] (a) CR²⁹R³⁰;

[0975] (b) oxygen; or

[0976] (c) sulfur;

[0977] R²⁹ and R³⁰ are each independently:

[0978] (a) hydrogen;

[0979] (b) lower alkyl;

[0980] (c) (CH₂)_(o)—OD¹;

[0981] (d) halo; or

[0982] R²⁹ and R³⁰ taken together are an oxo group;

[0983] s is an integer from 2 to 4;

[0984] R⁸, D¹, T, U, K and o are as defined herein;

[0985] with the proviso that the compounds of Formula IV must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[0986] Another embodiment of the present invention provides compounds ofthe Formula (V):

[0987] wherein:

[0988] X⁵ is:

[0989] (a) oxygen; or

[0990] (b) sulfur;

[0991] R³¹ is:

[0992] (a) alkoxy;

[0993] (b) haloalkoxy preferably —OCH₂F, —OCHF₂, or —OCHF₂;

[0994] (c) alkylthio;

[0995] (d) haloalkyl, preferably CF₃;

[0996] (e) halo; or

[0997] (f) lower alkyl;

[0998] R³², R³³, R³⁴, R³⁵, R³⁶ and R³⁷ are each independently:

[0999] (a) hydrogen;

[1000] (b) halo, preferably F or Cl;

[1001] (c) lower alkyl;

[1002] (d) cycloalkyl;

[1003] (e) haloalkyl, preferably CF₃, CF₂H or CFH₂;

[1004] (f) —OD¹;

[1005] (g) —OR⁴³;

[1006] (h) —SD¹;

[1007] (i) —SR⁴³;

[1008] (j) —S(O)R⁴³;

[1009] (k) —S(O)₂R⁴³;

[1010] (l) unsubstituted, mono- or di-substituted benzyl, wherein thesubstituents are each independently:

[1011] (1) haloalkyl, preferably CF₃;

[1012] (2) CN;

[1013] (3) halo;

[1014] (4) lower alkyl;

[1015] (5) —OR⁴³;

[1016] (6) —SR⁴³;

[1017] (7) —S(O)R⁴³; or

[1018] (8) —S(O)₂R⁴¹;

[1019] (m) phenyl or mono- or di-substituted phenyl, wherein thesubstituents are each independently:

[1020] (1) haloalkyl, preferably CF₃;

[1021] (2) CN;

[1022] (3) halo;

[1023] (4) lower alkyl;

[1024] (5) —OR⁴³;

[1025] (6) —SR⁴³;

[1026] (7) —S(O)R⁴³; or

[1027] (8) —S(O)₂R⁴¹; or

[1028] R³² together with R³³ form an oxo group; or

[1029] R³⁴ together with R³⁵ form an oxo group; or

[1030] R³⁶ together with R³⁷ form an oxo group; or

[1031] R³² and R³³ are joined so that, together with the carbon atom towhich they are attached, they form a saturated monocyclic ring of 3, 4,5, 6 or 7 members, and, optionally, contain one heteroatom which ispreferably oxygen; or

[1032] R³³ and R³⁴ are joined so that, together with the carbon atoms towhich they are attached, they form a saturated or aromatic monocyclicring of 3, 4, 5, 6 or 7 members; or

[1033] R³³ and R³⁶ are joined so that, together with the carbon atoms towhich they are attached, they form a saturated or aromatic monocyclicring of 3, 4, 5, 6 or 7 members; or

[1034] R³⁴ and R³⁵ are joined so that, together with the carbon atom towhich they are attached, they form a saturated monocyclic ring of 3, 4,5, 6 or 7 members, and optionally, contain one heteroatom which ispreferably oxygen; or

[1035] R³⁴ and R³⁶ are joined so that, together with the carbon atoms towhich they are attached, they form a saturated or aromatic monocyclicring of 3, 4, 5, 6 or 7 members; or

[1036] R³⁶ and R³⁷ are joined so that, together with the carbon atom towhich they are attached, they form a saturated monocyclic ring of 3, 4,5, 6 or 7 members, and, optionally, contain one heteroatom which ispreferably oxygen;

[1037] R³⁸ and R³⁹ are hydrogen or R³⁸ and R³⁹ when taken together areoxo;

[1038] R⁴⁰, R⁴¹ and R⁴² are each independently:

[1039] (a) hydrogen;

[1040] (b) halo;

[1041] (c) lower alkyl;

[1042] (d) alkoxy;

[1043] (e) alkylthio;

[1044] (f) —S(O)-lower alkyl;

[1045] (g) haloalkyl, preferably CF₃;

[1046] (h) CN;

[1047] (i) —N₃;

[1048] (j) —NO₂;

[1049] (k) —SCF₃; or

[1050] (l) —OCF₃;

[1051] R⁴³ is:

[1052] (a) lower alkyl; or

[1053] (b) benzyl, optionally mono- or di-substituted, wherein thesubstituents are each independently:

[1054] (1) haloalkyl, preferably CF₃;

[1055] (2) CN;

[1056] (3) halo; or

[1057] (4) lower alkyl;

[1058] alternatively, X⁵ and U taken together with the carbon atom towhich they are attached form a 5-, 6-, or 7-membered heterocyclic ring;

[1059] n at each occurrence is an integer from 0 to 1; and

[1060] D¹, U and K are as defined herein;

[1061] with the proviso that the compounds of Formula V must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1062] Another embodiment of the present invention provides compounds ofthe Formula (VI):

[1063] wherein:

[1064] X⁶ is:

[1065] (a) oxygen;

[1066] (b) sulfur;

[1067] (c) CH₂;

[1068] (d) —S(O)_(o);

[1069] (e) —NH; or

[1070] (f) —C(O);

[1071] Z⁶ is:

[1072] (a) K;

[1073] (b) —C(O)CH₃; or

[1074] (c) hydrogen;

[1075] R⁴⁵ is:

[1076] (a) lower alkyl; or

[1077] (b) mono-, di-, tri-, tetra- or per-substituted lower alkyl,wherein the substituent is halo, preferably fluoro;

[1078] R⁴⁶ is:

[1079] (a) mono or disubstituted aromatic ring of 5 atoms containing oneO, S or N atom, and, optionally, 1, 2 or 3 additional N atoms, whereinthe substituents are each independently:

[1080] (1) hydrogen;

[1081] (2) lower alkyl;

[1082] (3) halo;

[1083] (4) —O-lower alkyl;

[1084] (5) —S-lower alkyl;

[1085] (6) haloalkyl, preferably CF₃;

[1086] (7) —COCH₃; or

[1087] (8) —S(O)₂-lower alkyl;

[1088] (b) mono or disubstituted aromatic ring of 6 atoms containing 0,1, 2, 3 or 4 nitrogen atoms, wherein the substituents are eachindependently:

[1089] (1) hydrogen;

[1090] (2) lower alkyl;

[1091] (3) halo;

[1092] (4) —O-lower alkyl;

[1093] (5) —S-lower alkyl;

[1094] (4) —O-haloalkyl;

[1095] (5) —S-haloalkyl;

[1096] (6) haloalkyl, preferably CF₃;

[1097] (7) CN;

[1098] (8) —N₃;

[1099] (9) —COCH₃;

[1100] (10) —S(O)₂-lower alkyl;

[1101] (11) alkenyl; or

[1102] (12) alkynyl;

[1103] (c) cycloalkylalkyl;

[1104] (d) unsubstituted, mono-, di-, tri-, or tetra substituted phenylor naphthyl, wherein the substituents are each independently:

[1105] (1) halo;

[1106] (2) CN;

[1107] (3) haloalkyl, preferably CF₃;

[1108] (4) —N₃;

[1109] (5) vinyl;

[1110] (6) acetylenyl;

[1111] (7) lower alkyl;

[1112] (8) alkoxy;

[1113] (9) haloalkoxy;

[1114] (10) alkylthio; or

[1115] (11) haloalkylthio;

[1116] (e) unsubstituted, mono-, di-, tri-, or tetra substitutedbenzoheteroaryl, wherein the substituents are each independently:

[1117] (1) halo;

[1118] (2) CN; or

[1119] (3) haloalkyl, preferably CF₃;

[1120] (f) substituted lower alkyl;

[1121] (g) substituted alkenyl;

[1122] (h) cycloalkyl; or

[1123] (i) lower alkyl-O-lower alkyl;

[1124] R⁴⁷ is:

[1125] (a) —C(O)-lower alkyl;

[1126] (b) —CN;

[1127] (c) —CO₂D¹;

[1128] (d) —CO₂-lower alkyl ester;

[1129] (e) —C(O)—NHD¹;

[1130] (f) —S(O)-lower alkyl;

[1131] (g) —S(O)₂-lower alkyl;

[1132] (h) —NO₂;

[1133] (i) haloalkyl, preferably CF₃;

[1134] (j) halo;

[1135] (k) K;

[1136] (l) —S(O)_(o)NR¹⁰R¹¹; or

[1137] (m) —S(O)_(o)NR¹²R¹³;

[1138] R⁴⁸ is:

[1139] (a) hydrogen; or

[1140] (b) lower alkyl; or

[1141] R⁴⁷ and R⁴⁸ taken together with the atoms to which they areattached form a 5, 6, or 7-membered unsubstituted, mono-, di-, ortrisubstituted saturated or unsaturated cyclic ring optionallycontaining a —S(O)₂-group, wherein the substituents are eachindependently:

[1142] (a) oxo;

[1143] (b) lower alkyl;

[1144] (c) OD¹; or

[1145] (d) ═N—OD¹;

[1146] R¹⁰, R¹¹, R¹², R¹³, K, D¹ and o are as defined herein;

[1147] with the proviso that the compounds of Formula VI must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1148] Another embodiment of the present invention provides compounds ofFormula (VII):

[1149] wherein:

[1150] X⁷ is:

[1151] (a) oxygen;

[1152] (b) sulfur;

[1153] (c) —NR⁵¹;

[1154] (d) —N—O—R⁵²; or

[1155] (e) —N —NR⁵²R⁵³;

[1156] Y⁷ is:

[1157] (a) hydrogen;

[1158] (b) halo;

[1159] (c) lower alkyl;

[1160] (d) alkenyl; or

[1161] (e) alkynyl;

[1162] Z⁷ is:

[1163] (a) —C(O)—;

[1164] (b) oxygen;

[1165] (c) —S(O)_(o)—;

[1166] (d) —NR⁹³—; or

[1167] (e) covalent bond;

[1168] R⁴⁹ is:

[1169] (a) R³; or

[1170] (b) R⁴;

[1171] R⁵⁰ and R^(50′) are each independently:

[1172] (a) hydrogen;

[1173] (b) halo;

[1174] (c) lower alkyl;

[1175] (d) aryl;

[1176] (e) arylalkyl;

[1177] (f) cycloalkyl;

[1178] (g) cycloalkylalkyl;

[1179] (h) —OD¹;

[1180] (i) lower alkyl-OD¹;

[1181] (j) carboxamido;

[1182] (k) amidyl; or

[1183] (l) K;

[1184] R⁵¹ is:

[1185] (a) lower alkyl;

[1186] (b) alkenyl;

[1187] (c) cycloalkyl;

[1188] (d) cycloalkylalkyl;

[1189] (e) aryl;

[1190] (f) arylalkyl;

[1191] (g) heterocyclic ring; or

[1192] (h) lower alkyl-heterocyclic ring;

[1193] R⁵² and R⁵³ are each independently:

[1194] (a) lower alkyl;

[1195] (b) cycloalkyl;

[1196] (c) cycloalkylalkyl;

[1197] (d) aryl;

[1198] (e) arylalkyl;

[1199] (f) heterocyclic ring; or

[1200] (g) heterocyclicalkyl;

[1201] R⁹³ is:

[1202] (a) hydrogen; or

[1203] (b) lower alkyl;

[1204] R¹, R³, R⁴, K, D¹and o are as defined herein;

[1205] with the proviso that the compounds of Formula VII must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1206] Another embodiment of the present invention provides compounds ofthe Formula (VIII):

[1207] wherein:

[1208] X⁸ is:

[1209] (a) oxygen;

[1210] (b) sulfur;

[1211] (c) NR_(i); or

[1212] (d) —CR⁵⁸R⁵⁹;

[1213] A¹, A², A³, and A⁴ are each independently carbon or nitrogen,with the proviso that at least two of A¹, A², A³, and A⁴ are carbonatoms;

[1214] R⁵⁴ is:

[1215] (a) haloalkylalkyl, preferably fluoroalkylalkyl;

[1216] (b) halo;

[1217] (c) alkylthio;

[1218] (d) alkoxy;

[1219] (e) —NO₂;

[1220] (f) CN;

[1221] (g) lower alkyl-CN;

[1222] (h) heterocyclic ring;

[1223] (i) lower alkyl;

[1224] (j) arylalkyl;

[1225] (k) cycloalkyl; or

[1226] (l) phenyl or mono- or di-substituted phenyl, wherein thesubstituents are each independently:

[1227] (1) alkylthio;

[1228] (2) nitro; or

[1229] (3) alkylsulfonyl;

[1230] R⁵⁵ is:

[1231] (a) —CO₂D¹;

[1232] (b) —C(O)—N (R⁸)(R⁸);

[1233] (c) —CO₂-lower alkyl;

[1234] (d) —C(O)—N(D¹)—S(O)₂—(C(R_(e))(R_(f)))_(p)—U—V; or

[1235] (e) —CO₂-lower alkyl-U—V;

[1236] R⁵⁶ is:

[1237] (a) hydrogen;

[1238] (b) phenyl;

[1239] (c) thienyl;

[1240] (d) alkynyl;

[1241] (e) alkenyl; or

[1242] (f) alkyl;

[1243] R_(g) is:

[1244] (a) hydrogen;

[1245] (b) lower alkyl;

[1246] (c) arylalkyl;

[1247] (d) alkoxy;

[1248] (e) aryloxy;

[1249] (f) arylalkoxy;

[1250] (g) haloalkyl;

[1251] (h) haloalkoxy;

[1252] (i) alkylamino;

[1253] (j) arylamino;

[1254] (k) arylalkylamino;

[1255] (l) nitro;

[1256] (m) sulfonamido;

[1257] (n) carboxamido;

[1258] (o) aryl;

[1259] (p) —C(O)-aryl; or

[1260] (q) —C(O)-alkyl;

[1261] alternatively, R_(g) and the monocyclic ring radical of which A¹,A², A³, and A⁴ comprise four of the six atoms are:

[1262] (a) naphthyl;

[1263] (b) quinolyl;

[1264] (c) isoquinolyl;

[1265] (d) quinolizinyl;

[1266] (e) quinoxalinyl; or

[1267] (f) dibenzofuryl;

[1268] R⁵⁸ and R⁵⁹ are each independently:

[1269] (a) hydrogen;

[1270] (b) lower alkyl;

[1271] (c) lower alkyl-phenyl;

[1272] (d) haloalkyl, preferably fluoroalkyl;

[1273] (e) halo;

[1274] (f) —NO₂;

[1275] (g) CN;

[1276] (h) lower alkyl-CN;

[1277] (i) alkoxy;

[1278] (j) alkylthio; or

[1279] (k) alkenyl;

[1280] alternatively, R⁵⁸ and R⁵⁹ taken together along with the atoms towhich they are attached are cycloalkyl;

[1281] R⁸, R_(i), R_(e), R_(f), D¹, U, V, a and p are as defined herein;

[1282] with the proviso that the compounds of Formula VIII must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1283] Another embodiment of the present invention provides compounds ofthe Formula (IX):

[1284] wherein:

[1285] X⁹ is —C(O)—U—D¹ and Y⁹ is —CH₂—CR⁵(R⁵′)—U—D¹′; or

[1286] X⁹ is —CH₂—CR⁵(R⁵′)—U—D¹ and Y⁹ is —C(O)—U—D¹; or

[1287] X⁹ and Y⁹ taken together are:

[1288] (a) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1289] (b) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—CR⁵(R⁵)—;

[1290] (c) —C(O)—(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—;

[1291] (d) —(CR⁴(R^(4′)))_(k)—CR⁵(R^(5′))—C(O)—; or

[1292] (e) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1293] wherein X⁹ is the first carbon atom of a, b, c, d and e;

[1294] R¹, R², R⁴, R⁴′, R⁵, R⁵′, U, D¹ and k are as defined herein;

[1295] with the proviso that the compounds of Formula IX contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1296] Another embodiment of the present invention provides compounds ofthe Formula (X):

[1297] wherein:

[1298] when side h, k, and j are single bonds, and side i and l are adouble bond, —X¹⁰—Y¹⁰—Z¹⁰— is:

[1299] when sides i, k and l are single bonds, and sides h and j aredouble bonds, —X¹⁰—Y¹⁰—Z¹⁰— is:

[1300] when side h and j are single bonds, and side k and i is a singleor a double bond, —X¹⁰—Y¹⁰—Z¹⁰— is:

[1301] P¹⁰ is:

[1302] (a) —N═;

[1303] (b) —NR³—;

[1304] (c) —O—; or

[1305] (d) —S—;

[1306] Q¹⁰ and Q^(10′) are each independently:

[1307] (a) CR⁶⁰; or

[1308] (b) nitrogen;

[1309] A¹⁰

B¹⁰—C¹⁰

D¹⁰— is:

[1310] (a) —CR⁴═CR^(4′)—CR⁵═CR^(5′)—;

[1311] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—C(O)—;

[1312] (c) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—CR⁴(R_(4′))—;

[1313] (d) —CR⁴(R^(4′))—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1314] (e) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—;

[1315] (f) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[1316] (g) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

[1317] (h) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1318] (i) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—C(O)—;

[1319] (j) —CR⁴(R^(4′))—O—C(O)—CR⁵(R^(5′))—;

[1320] (k) —O—C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1321] (l) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—O—;

[1322] (m) —CR⁴(R^(4′))—C(O)—O—CR⁵(R^(5′))—;

[1323] (n) —C(O)—O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1324] (o) —CR¹² (R¹³)—O—C(O)—;

[1325] (p) —C(O)—O—CR¹²(R¹³)—;

[1326] (q) —O—C(O)—CR¹²(R¹³)—;

[1327] (r) —CR¹²(R¹³)—C(O)—O—;

[1328] (s) —N═CR⁴CR^(4′)═CR⁵—;

[1329] (t) —CR⁴═N—CR^(4′)═CR⁵—;

[1330] (u) —CR⁴═CR^(4′—N═CR) ⁵—;

[1331] (v) —CR⁴═CR⁵—CR^(5′)═N—;

[1332] (w) —N═CR⁴CR^(4′)═N—;

[1333] (x) —N═CR⁴—N═CR^(4′)—;

[1334] (y) —CR⁴═N—CR^(4′)═N—;

[1335] (z) —S—CR⁴═N—;

[1336] (aa) —S—N═CR⁴—;

[1337] (bb) —N═N—NR³—;

[1338] (cc) —CR⁴═N—S—;

[1339] (dd) —N═CR⁴—S—;

[1340] (ee) —O—CR⁴═N—;

[1341] (ff) —O—N═CR⁴—; or

[1342] (gg) —N═CR⁴—O—;

[1343] —A^(10′)

B^(10′)

D^(10′)

is:

[1344] (a) —CR⁴═CR⁵—CR^(5′)═

[1345] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—CR⁴(R^(4′))—;

[1346] (c) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1347] (d) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[1348] (e) —N═CR⁴—CR⁵═;

[1349] (g) —N═N—CR⁴═;

[1350] (h) —N═N—NR³—;

[1351] (i) —N═N—N═;

[1352] (j) —N═CR⁴—NR³—;

[1353] (k) —N═CR⁴—N═;

[1354] (l) —CR⁴═N—NR³—;

[1355] (m) —CR⁴═N—N═;

[1356] (n) —CR⁴═N—CR⁵═;

[1357] (o) —CR⁴═CR⁵—NR³—;

[1358] (p) —CR⁴═CR⁵—N═;

[1359] (q) —S—CR⁴═CR⁵—;

[1360] (r) —O—CR⁴═CR⁵;

[1361] (s) —CR⁴═CR⁵—O—;

[1362] (t) —CR⁴═CR⁵—S—;

[1363] (u) —CR⁴═N—S—;

[1364] (v) —CR⁴═N—O—;

[1365] (w) —N═CR⁴—S—;

[1366] (x) —N═CR⁴—O—;

[1367] (y) —S—CR⁴═N—;

[1368] (z) —O—CR⁴═N—;

[1369] (aa) —N═N—S—;

[1370] (bb) —N═N—O—;

[1371] (cc) —S—N═N—;

[1372] (dd) —O—N═N—;

[1373] (ee) —CR⁴═CR⁵—S;

[1374] (ff) —CR⁴(R^(4′))—CR⁵(R^(5′))—S—;

[1375] (gg) —CR⁴(R^(4′))—CR⁵(R^(5′))—O—;

[1376] (hh) —S—CR⁴(R^(4′))—CR⁵(R^(5′))—; or

[1377] (ii) —O—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1378] R⁶⁰ and R⁶¹ are each independently:

[1379] (a) lower alkyl;

[1380] (b) haloalkyl, preferably fluoroalkyl;

[1381] (c) alkoxy;

[1382] (d) alkylthio;

[1383] (e) lower alkyl-OD¹;

[1384] (f) —C(O)H;

[1385] (h) —(CH₂)_(q)—CO₂-lower alkyl;

[1386] (i) —(CH₂)_(q)—CO₂D¹;

[1387] (j) —O—(CH₂)_(q)—S-lower alkyl;

[1388] (k) —(CH₂)_(q)—S-lower alkyl;

[1389] (l) —S(O)₂-lower alkyl;

[1390] (m) —(CH₂)_(q)—NR¹²R¹³; or

[1391] (n) —C(O)N(R⁸)(R⁸);

[1392] R¹, R², R³, R⁴, R^(4′), R⁵, R^(5′), R⁸, R¹², R¹³, T, D¹and q areas defined herein;

[1393] with the proviso that the compounds of Formula X must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1394] Another embodiment of the present invention provides compounds ofthe Formula (XI):

[1395] wherein:

[1396] X¹¹ is:

[1397] (a) oxygen; or

[1398] (b) CH₂;

[1399] Y¹¹ is:

[1400] (a) oxygen;

[1401] (b) —H₂;

[1402] (c) —N—OD¹;

[1403] (d) —N—O-lower alkyl;

[1404] (e) —N—O-aryl;

[1405] (f) —N—C(O)—O-lower alkyl;

[1406] (g) —N—N(R⁸)(R⁸); or

[1407] (h) —N—N(R⁸)—S(O)₂-lower alkyl;

[1408] R⁶², R⁶³, R⁶⁴ and R⁶⁵ are each independently:

[1409] (a) hydrogen;

[1410] (b) lower alkyl;

[1411] (c) alkoxy;

[1412] (d) halo;

[1413] (e) CN;

[1414] (f) OD¹;

[1415] (g) aryloxy;

[1416] (h) —NR¹²R¹³;

[1417] (i) —CF₃;

[1418] (j) —NO₂;

[1419] (k) alkylthio;

[1420] (l) —S(O)_(o)-lower alkyl;

[1421] (m) —C(O)N(R⁸)(R⁸);

[1422] (n) —CO₂D¹

[1423] (o) —CO₂-lower alkyl; or

[1424] (p) —NR⁸—C(O)-lower alkyl;

[1425] R⁶⁶ is:

[1426] (a) hydrogen;

[1427] (b) lower alkyl;

[1428] (c) alkenyl;

[1429] (d) alkoxyalkyl; or

[1430] (e) cycloalkylalkyl;

[1431] R⁸, R¹², R¹³, o, K and D¹ are as defined herein;

[1432] with the proviso that the compounds of Formula XI must contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1433] Another embodiment of the present invention provides compounds ofthe Formula (XII):

[1434] wherein:

[1435] X¹² is:

[1436] (e) —NR⁷³(R⁷⁴);

[1437] (f) hydrogen; or

[1438] (g) K;

[1439] Z¹² is:

[1440] (b) R⁶⁷;

[1441] R⁶⁷ is:

[1442] (a) hydrogen;

[1443] (b) lower alkyl;

[1444] (c) lower alkyl-OD¹;

[1445] (d) —OD¹;

[1446] (e) haloalkyl; or

[1447] (f)

[1448] R⁶⁸ is:

[1449] (a) lower alkyl;

[1450] (b) halo;

[1451] (c) alkoxy

[1452] (d) haloalkyl;

[1453] (e) alkylthio;

[1454] (f) haloalkylthio;

[1455] (g) —OCH₂—

[1456] (h) unsubstituted, mono-, or di-substituted heteroaryl, whereinthe heteroaryl is a monocyclic aromatic ring of 5 atoms, said ringhaving one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally 1, 2, or 3additional N atoms, and wherein said substituents are eachindependently:

[1457] (1) halo; or

[1458] (2) lower alkyl

[1459] (i) —S(O)_(o)-lower alkyl;

[1460] (j) —S(O)_(o)-lower haloalkyl;

[1461] (k) amino;

[1462] (l) alkylamino;

[1463] (m) dialkylamino;

[1464] (n) —N(H)SO₂-lower alkyl;

[1465] (o) N(H)SO₂-lower haloalkyl;

[1466] (p) nitro;

[1467] (q) cyano;

[1468] (r) —CO₂D¹;

[1469] (s) carboxylic ester;

[1470] (t) lower alkyl-OD¹;

[1471] (q) carboxamide; or

[1472] (r) —C(O)N(R¹²)D¹;

[1473] R⁶⁹ is:

[1474] (a) lower alkyl;

[1475] (b) hydrogen;

[1476] (c) alkoxy

[1477] (d) mono-, di-, tri, tetra- or penta-substituted phenyl, whereinthe substituent are each independently:

[1478] (1) hydrogen;

[1479] (2) halo;

[1480] (3) alkoxy;

[1481] (4) alkylthio;

[1482] (5) —S(O)_(o)-lower alkyl;

[1483] (6) lower alkyl;

[1484] (7) haloalkyl;

[1485] (8) —CO₂D¹;

[1486] (9) -lower alkyl—CO₂D¹;

[1487] (10) —OD¹;

[1488] (11) -lower alkyl-OD¹; or

[1489] (12) haloalkoxy;

[1490] (e) mono-, di-, or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:

[1491] (1) hydrogen;

[1492] (2) halo;

[1493] (3) lower alkyl;

[1494] (4) alkoxy;

[1495] (5) alkylthio;

[1496] (6) aryloxy;

[1497] (7) arylthio;

[1498] (8) —CO₂D¹;

[1499] (9) —C(O)NH(D¹)

[1500] (10) haloalkyl; or

[1501] (11) —OD¹;

[1502] R⁷⁰ is:

[1503] (a) lower alkyl;

[1504] (b) hydrogen; or

[1505] (c) mono- or di-substituted phenyl, wherein the substituent areeach independently:

[1506] (1) hydrogen;

[1507] (2) halo;

[1508] (3) alkoxy;

[1509] (4) haloalkyl; or

[1510] (5) lower alkyl;

[1511] R⁷¹ is:

[1512] (a) benzoyl, or mono-, or disubstituted benzoyl, wherein thesubstituents are each independently:

[1513] (1) halo;

[1514] (2) lower alkyl; or

[1515] (3) alkoxy;

[1516] (b) benzyl, mono- or disubstituted benzyl, wherein thesubstituents are each independently:

[1517] (1) halo;

[1518] (2) lower alkyl; or

[1519] (3) alkoxy;

[1520] (c) lower alkyl-pyridinyl, or unsubstituted, mono-, ordisubstituted pyridinyl, wherein the substituents are eachindependently:

[1521] (1) halo;

[1522] (2) lower alkyl; or

[1523] (3) alkoxy;

[1524] (d) —C(O)-pyridinyl, or mono-, or disubstituted —C(O)-pyridinylwherein the substituents are each independently:

[1525] (1) halo;

[1526] (2) lower alkyl; or

[1527] (3) alkoxy;

[1528] (e) hydrogen;

[1529] (f) aryl;

[1530] (g) cycloalkyl;

[1531] (h) cycloalkylalkyl;

[1532] R⁷² is:

[1533] (a) lower alkenyl-CO₂D¹; or

[1534] (b) K;

[1535] R⁷³ is unsubstituted or mono substituted lower alkyl, wherein thesubstituents are each independently:

[1536] (a) hydroxy;

[1537] (b) alkoxy;

[1538] (c) nitro;

[1539] (c) —NH₂;

[1540] (d) alkylamino;

[1541] (e) dialkylamino;

[1542] (f) carboxyl;

[1543] (g) carboxylic ester; or

[1544] (h) carboxamide;

[1545] R⁷⁴ is:

[1546] (a) hydrogen;

[1547] (b) lower alkyl; or

[1548] (c) —C(O)R⁷⁶;

[1549] R⁷⁵ is:

[1550] (a) lower alkyl;

[1551] (b) haloalkyl

[1552] (c) substituted lower alkyl;

[1553] (d) cycloalkyl;

[1554] (e) unsubstituted, mono-, di- or tri-substituted phenyl ornaphthyl, wherein the substituents are each independently:

[1555] (1) halo;

[1556] (2) alkoxy;

[1557] (3) —S(O)_(o)-lower alkyl;

[1558] (4) hydroxy;

[1559] (5) —S(O)_(o)-haloalkyl;

[1560] (6) lower alkyl;

[1561] (7) haloalkyl;

[1562] (8) —CO₂D¹;

[1563] (9) —CO₂-lower alkyl;

[1564] (10) —S(O)₂NR⁸(D¹);

[1565] (11) -lower alkyl-O-lower alkyl;

[1566] (12) —CN;

[1567] (13) lower alkyl-OD¹;

[1568] (14) arylalkoxy;

[1569] (15) —C(O)NR⁸(D¹); or

[1570] (16) aryl;

[1571] (f) mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is selected from S, O, or N, and, optionally, 1, 2,or 3 additional N atoms; or the heteroaryl is a monocyclic ring of 6atoms, said ring having one heteroatom which is N, and, optionally, 1,2, 3, or 4 additional N atoms; wherein the substituents are eachindependently:

[1572] (1) halo;

[1573] (2) alkoxy;

[1574] (3) —S(O)_(o)-lower alkyl;

[1575] (4) hydroxy;

[1576] (5) —S(O)_(o)-haloalkyl;

[1577] (6) lower alkyl;

[1578] (7) haloalkyl;

[1579] (8) —CO₂D¹;

[1580] (9) —Co₂-lower alkyl;

[1581] (10) —S(O)₂NR⁸(D¹);

[1582] (11) -lower alkyl-O-lower alkyl;

[1583] (12) —N(D¹)S(O)₂-lower alkyl;

[1584] (13) lower alkyl-OD¹;

[1585] (14) —N(D¹)S(O)₂-haloalkyl;

[1586] (15) —C(O)NR⁸(D¹); or

[1587] (16) aryl;

[1588] R⁷⁶ is:

[1589] (a) alkyl;

[1590] (b) substituted alkyl;

[1591] (c) alkyl-N(D¹)S(O)₂-aryl;

[1592] (d) substituted alkyl-cycloalkyl;

[1593] (e) substituted alkyl-heterocyclic ring; or

[1594] (f) arylalkoxy;

[1595] R77 is:

[1596] (a) —OD¹;

[1597] (b) alkoxy; or

[1598] (c) —NR⁷⁸R⁷⁹;

[1599] R⁷⁸ and R⁷⁹ are each independently:

[1600] (a) hydrogen;

[1601] (b) hydroxy;

[1602] (c) alkoxy;

[1603] (d) lower alkyl; or

[1604] (e) substituted lower alkyl; or

[1605] R⁷⁸ and R⁷⁹ taken together with the nitrogen to which they areattached form a heterocyclic ring;

[1606] R⁸⁰ and R⁸¹ are each independently:

[1607] (a) hydrogen;

[1608] (b) lower alkyl; or

[1609] (c) halo;

[1610] R⁸⁹ and R^(89′) are each independently:

[1611] (a) hydrogen; or

[1612] (b) lower alkyl; or

[1613] R⁸⁹ and R^(89′) taken together with the carbon to which they areattached form a cycloalkyl ring;

[1614] m is an integer from 0 to 6;

[1615] D¹, R¹, R⁸, R¹², K, X⁵, a, p and o are as defined herein; and

[1616] with the proviso that the compounds of Formula XII must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1617] Another embodiment of the present invention provides compounds ofthe Formula (XIII):

[1618] wherein:

[1619] X¹³ and y¹³ are each independently:

[1620] (a) ═C(H)—; or

[1621] (b) ═N—;

[1622] R⁹⁰ is:

[1623] (a) lower alkyl;

[1624] (b) lower alkyl-OD¹;

[1625] (c) alkenyl;

[1626] (d) lower alkyl-CN;

[1627] (e) lower alkyl-CO₂D¹;

[1628] (f) aryl;

[1629] (g) heterocyclic ring; or

[1630] (i) heterocyclicalkyl;

[1631] R⁹¹ is:

[1632] (a) mono-, di- or tri-substituted phenyl, wherein thesubstituents are each independently:

[1633] (1) hydrogen;

[1634] (2) halo;

[1635] (3) alkoxy;

[1636] (4) alkylthio;

[1637] (5) CN;

[1638] (6) haloalkyl;

[1639] (7) lower alkyl;

[1640] (8) —CO₂D¹;

[1641] (9) —CO₂-lower alkyl;

[1642] (10) lower alkyl-OD¹;

[1643] (11) lower alkyl-NR¹²NR¹³;

[1644] (12) lower alkyl-CO₂D¹; or

[1645] (13)—OD¹;

[1646] (b) mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; wherein the substituents are each independently:

[1647] (1) hydrogen;

[1648] (2) halo;

[1649] (3) alkoxy;

[1650] (4) alkylthio;

[1651] (5) CN;

[1652] (6) haloalkyl;

[1653] (7) lower alkyl;

[1654] (8) —CO₂D¹;

[1655] (9) —CO₂-lower alkyl;

[1656] (10) lower alkyl-OD¹;

[1657] (11) lower alkyl-NR¹²R¹³;

[1658] (12) lower alkyl-CO₂D¹; or

[1659] (13) —OD¹;

[1660] D¹, R¹, R¹², and R¹³, are as defined herein; and

[1661] with the proviso that the compounds of Formula XIII must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1662] Another embodiment of the present invention provides compounds ofthe Formula (XIV):

[1663] wherein:

[1664] X¹⁴ is:

[1665] (a) —C(O)—; or

[1666] (b) —C(S)—;

[1667] Y¹⁴ is:

[1668] (a) —O—; or

[1669] (b) —S—;

[1670] A¹⁴

B¹⁴

D¹⁴ is:

[1671] (a) —CR⁴═CR^(4′)—CR⁵═CR^(5′)—;

[1672] (b) —CR⁴(R^(4′))—CR⁵(R^(5′))—C(O)—;

[1673] (c) —CR⁴(R^(4′))—C(O)—CR⁵(R^(5′))—;

[1674] (d) —C(O)—CR⁴(R^(4′))—CR⁵(R^(5′))—;

[1675] (e) —CR⁴(R⁵)—O—C(O)—;

[1676] (f) —C(O)—O—CR⁴(R⁵)—;

[1677] (g) —O—C(O)—CR⁴(R⁵)—;

[1678] (h) —S—N═CR⁴—;

[1679] (i) —O—N═CR⁴—;

[1680] (j) —CR⁴(R⁵)—NR³—C(O)—;

[1681] (k) —C(O)—NR³—CR⁴(R⁵)—;

[1682] (l) —NR³—C(O)—CR⁴(R⁵)—;

[1683] (m) —CR⁴(R⁵)—S—C(O)—;

[1684] (n) —C(O)—S—CR⁴(R⁵)—;

[1685] (o) —S—C(O)—CR⁴(R⁵)—;

[1686] (p) —CR⁴═CR^(4′)—C(O)—;

[1687] (q) —C(O)—CR⁴═CR⁴—;

[1688] (r) —O—CR⁴═CR^(4′)—;

[1689] (s) —S—CR⁴═CR^(4′);

[1690] (t) —NR³—CR⁴═CR⁵—;

[1691] (u) —S—NR³—C(O)—;

[1692] (v) —O—NR³—C(O)—; or

[1693] (w) —NR³—N═CR⁴—;

[1694] R¹, R², R³, R⁴, R^(4′), R⁵ and R^(5′) are as defined herein; and

[1695] with the proviso that the compounds of Formula XIV must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1696] Another embodiment of the present invention provides compounds ofthe Formula (XV):

[1697] wherein:

[1698] X¹⁵ is:

[1699] (a) —C(O)—;

[1700] (b) —CH₂—;

[1701] (c) —CH(OD¹)—;

[1702] (d) —C═N—O-lower alkyl-;

[1703] (e) —O—;

[1704] (f) —S(O)_(o)—;

[1705] (g) —NR⁹²; or

[1706] (g) covalent bond;

[1707] Y¹⁵ is:

[1708] (a) aryl; or

[1709] (b) cycloalkyl;

[1710] Z¹⁵ is:

[1711] (a) hydrogen;

[1712] (b) alkyl;

[1713] (c) haloalkyl;

[1714] (d) cycloalkyl;

[1715] (e) alkoxy;

[1716] (f) alkylthio;

[1717] (g) cycloalkylalkylthio;

[1718] (h) cycloalkylalkoxy;

[1719] (i) —OD¹;

[1720] (j) halo;

[1721] (k) cyano;

[1722] (l) —C(O)OD¹;

[1723] (m) —C(O)-lower alkyl;

[1724] R⁹² is:

[1725] (a) hydrogen;

[1726] (b) lower alkyl;

[1727] (c) —C(O)-lower alkyl; or

[1728] (d) K;

[1729] R¹, D¹, K and o are as defined herein; and

[1730] with the proviso that the compounds of Formula XV contain atleast one nitrite, nitrate, thionitrite or thionitrate group.

[1731] Another embodiment of the present invention provides compounds ofthe Formula (XVI):

[1732] (a) hydrogen;

[1733] (b) halogen;

[1734] (c) methyl; or

[1735] (d) ethyl;

[1736] Z¹⁶ is:

[1737] (a) hydrogen; or

[1738] (b) methyl;

[1739] R⁹³ is:

[1740] (a) chloro; or

[1741] (b) fluoro;

[1742] R⁹⁴ and R^(94′) are each independently:

[1743] (a) hydrogen; or

[1744] (b) fluoro;

[1745] R⁹⁵ is:

[1746] (a) chloro;

[1747] (b) fluoro;

[1748] (c) hydrogen;

[1749] (d) methyl;

[1750] (e) ethyl;

[1751] (f) methoxy;

[1752] (g) ethoxy; or

[1753] (i) hydroxy;

[1754] R⁹⁶ is:

[1755] (a) chloro;

[1756] (b) fluoro;

[1757] (c) trifluoromethyl; or

[1758] (d) methyl;

[1759] R⁹⁸ is:

[1760] (a) lower alkyl;

[1761] (b) lower alkenyl;

[1762] (c) alkoxy; or

[1763] (d) alkylthio;

[1764] K and X¹³ are as defined herein; and

[1765] with the proviso that the compounds of Formula XVI must containat least one nitrite, nitrate, thionitrite or thionitrate group.

[1766] Compounds of the present invention that have one or moreasymmetric carbon atoms may exist as the optically pure enantiomers,pure diastereomers, mixtures of enantiomers, mixtures of diastereomers,racemic mixtures of enantiomers, diastereomeric racemates or mixtures ofdiastereomeric racemates. The present invention includes within itsscope all such isomers and mixtures thereof.

[1767] Another aspect of the present invention provides processes formaking the novel compounds of the invention and to the intermediatesuseful in such processes. The reactions are performed in solventsappropriate to the reagents and materials used are suitable for thetransformations being effected. It is understood by one skilled in theart of organic synthesis that the functionality present in the moleculemust be consistent with the chemical transformation proposed. This will,on occasion, necessitate judgment by the routineer as to the order ofsynthetic steps, protecting groups required, and deprotectionconditions. Substituents on the starting materials may be incompatiblewith some of the reaction conditions required in some of the methodsdescribed, but alternative methods and substituents compatible with thereaction conditions will be readily apparent to one skilled in the art.The use of sulfur and oxygen protecting groups is well known forprotecting thiol and alcohol groups against undesirable reactions duringa synthetic procedure and many such protecting groups are known anddescribed by, for example, Greene and Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, New York (1999).

[1768] The chemical reactions described herein are generally disclosedin terms of their broadest application to the preparation of thecompounds of this invention. Occasionally, the reactions may not beapplicable as described to each compound included within the disclosedscope. The compounds for which this occurs will be readily recognized byone skilled in the art. In all such cases, either the reactions can besuccessfully performed by conventional modifications known to oneskilled in the art, e.g., by appropriate protection of interferinggroups, by changing to alternative conventional reagents, by routinemodification of reaction conditions, and the like, or other reactionsdisclosed herein or otherwise conventional, will be applicable to thepreparation of the corresponding compounds of this invention. In allpreparative methods, all starting materials are known or readilyprepared from known starting materials.

[1769] The compounds of Formulas (I), (II), (III), (IV), (V), (VI),(VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) canbe synthesized by one skilled in the art following the methods andexamples described herein. The synthesis of the parent COX-2 inhibitors(i.e. non-nitrosated and/or non-nitrosylated COX-2 inhibitors) aredisclosed in, for example, U.S. Pat. Nos. 5,344,991, 5,393,790,5,466,823, 5,474,995, 5,486,534, 5,504,215, 5,508,426, 5,510,496,5,516,907, 5,521,207, 5,536,752, 5,550,142, 5,563,165, 5,616,601,5,620,999, 5,677,318, 5,668,161, 5,691,374, 5,698,584, 5,710,140,5,753,688, 5,859,257, 5,908,858, 5,945,539, 5,994,381, 6,080,876,6,083,969 and 6,071,954 and in WO 91/19708, WO 94/15932, WO 94/26731, WO94/27980, WO 95/00501, WO 95/11883, WO 95/15315, WO 95/15316, WO95/15317, WO 95/15318, WO 95/18799, WO 95/21817, WO 95/30652, WO96/30656, WO 96/03387, WO 96/03392, WO 96/03385, WO 96/03387, WO96/03388, WO 96/09293, WO 96/09304, WO 96/16934, WO 96/19462, WO96/19463, WO 96/19469, WO 96/25405, WO 96/36617, WO 96/36623, WO97/11704, WO 97/13755, WO 97/27181, WO 97/14691, WO 97/16435, WO97/34882, WO 97/36863, WO 97/40012, WO 97/45420, WO 98/00416, WO98/11080, WO 98/22422, WO 98/41516, WO 98/46594, WO 98/52937, WO99/15531, WO 99/23087, WO 99/33796, WO 99/25695, WO 99/61016, WO99/62884 and WO 99/64415 and in EP 0 745 596 A1, EP 0 087 629 B1, EP 0418 845 B1, EP 0 554 829 A2,EP 0 863 134 A1, EP 1 006 114 A1 for theparent compounds of Formulas (I) and (II); and in U.S. Pat. Nos.5,733,909, 5,789,413 and 5,849,943 and in WO 96/13483, WO 97/28120 andWO 97/28121 for the parent compounds of Formula (III); and in U.S. Pat.No. 5,861,419 and 6,001,843 and in WO 96/10012, WO 96/16934, WO96/24585, WO 98/03484, WO 98/24584, WO 98/47871, WO 99/14194 and WO99/14195 for the parent compounds of Formula (IV); and in U.S. Pat. Nos.5,436,265, 5,510,368, 5,604,253 and 5,639,780 and in WO 96/37467, WO96/37468, WO 96/37469, WO 98/39330 and WO 00/40087 for the parentcompounds of Formula (V); and in U.S. Pat. Nos. 5,409,9444, 5,604,260,5,968,859, 5,776,984, 5,968,958 and in WO 94/13635, WO 94/20480, WO96/23786, WO 97/03953, WO 98/33769 and WO 99/15503 for the parentcompounds of Formula (VI); and in WO 98/41511, WO 99/10331, WO 99/10332and WO 00/24719 for the parent compounds of Formula (VII); and in WO98/47890 and WO 00/23443 for the parent compounds of Formula (VIII), andin U.S. Pat. No. 5,807,873 and WO 98/43966 for the parent compounds ofFormula (IX); and in U.S. Pat. Nos. 5,521,213 and 5,552,422 and in WO96/06840, WO 96/21667, WO 96/31509, WO 99/12930, WO 00/08024 and WO00/26216 for the parent compounds of Formula (X); and in U.S. Pat. Nos.5,776,967, 5,824,699 and 5,830,911 and in WO 98/04527 for the parentcompounds of Formula (XI); and in U.S. Pat. Nos. 5,750,558 and 5,756,531and in WO 97/41100, WO 98/05639, WO 98/21195, WO 98/57924, WO 99/05104and WO 99/35130 for the parent compounds of Formula (XII); and in WO99/61436 for the parent compounds of Formula (XIII); and in WO 00/10993for the parent compounds of Formula (XIV); and in WO 98/32732 for theparent compounds of Formula (XV); and in WO 97/09977, WO 99/11605 and WO99/41224 for the parent compounds of Formula (XVI); the disclosures ofeach of which are incorporated by reference herein in their entirety.The parent COX-2 inhibitor compounds can then be nitrosated and/ornitrosylated through one or more sites-such as oxygen, sulfur and/ornitrogen using the methods described in the examples herein and usingconventional methods known to one skilled in the art. For example, knownmethods for nitrosating and nitrosylating compounds are described inU.S. Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; andOae et al, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosuresof each of which are incorporated by reference herein in their entirety.The methods of nitrosating and/or nitrosylating the compounds describedin the examples herein and in these references can be applied by oneskilled in the art to produce any of the nitrosated and/or nitrosylatedCOX-2 inhibitors described herein.

[1770] The compounds of the present invention include the parent COX-2inhibitors, including those described herein, which have been nitrosatedand/or nitrosylated through one or more sites such as oxygen (hydroxylcondensation), sulfur (sulfhydryl condensation) and/or nitrogen. Thenitrosated and/or nitrosylated COX-2 inhibitors of the present inventiondonate, transfer or release a biologically active form of nitrogenmonoxide (i.e., nitric oxide).

[1771] Nitrogen monoxide can exist in three forms: NO− (nitroxyl), NO.(uncharged nitric oxide) and NO⁺ (nitrosonium). NO. is a highly reactiveshort-lived species that is potentially toxic to cells. This is criticalbecause the pharmacological efficacy of NO depends upon the form inwhich it is delivered. In contrast to the nitric oxide radical (NO.),nitrosonium (NO⁺) does not react with O₂ or O₂ ⁻ species, andfunctionalities capable of transferring and/or releasing NO⁺ and NO− arealso resistant to decomposition in the presence of many redox metals.Consequently, administration of charged NO equivalents (positive and/ornegative) is a more effective means of delivering a biologically activeNO to the desired site of action.

[1772] Compounds contemplated for use in the present invention (e.g.,nitrosated and/or nitrosylated COX-2 inhibitors) are, optionally, usedin combination with nitric oxide and compounds that release nitric oxideor otherwise directly or indirectly deliver or transfer a biologicallyactive form of nitrogen monoxide to a site of its intended activity,such as on a cell membrane in vivo.

[1773] The term “nitric oxide” encompasses uncharged nitric oxide (NO.)and charged nitrogen monoxide species, preferably charged nitrogenmonoxide species, such as nitrosonium ion (NO⁺) and nitroxyl ion (NO−).The reactive form of nitric oxide can be provided by gaseous nitricoxide. The nitrogen monoxide releasing, delivering or transferringcompounds have the structure F—NO, wherein F is a nitrogen monoxidereleasing, delivering or transferring moiety, and include any and allsuch compounds which provide nitrogen monoxide to its intended site ofaction in a form active for its intended purpose. The term “NO adducts”encompasses any nitrogen monoxide releasing, delivering or transferringcompounds, including, for example, S-nitrosothiols, nitrites, nitrates,S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines, (NONOates),(E)-alkyl-2-((E)-hydroxyimino)-5-nitro-3-hexene amines or amides,nitrosoamines, furoxans as well as substrates for the endogenous enzymeswhich synthesize nitric oxide. The “NO adducts” can bemono-nitrosylated, poly-nitrosylated, mono-nitrosated and/orpoly-nitrosated at a variety of naturally susceptible or artificiallyprovided binding sites for biologically active forms of nitrogenmonoxide.

[1774] One group of NO adducts is the S-nitrosothiols, which arecompounds that include at least one —S—NO group. These compounds includeS-nitroso-polypeptides (the term “polypeptide” includes proteins andpolyamino acids that do not possess an ascertained biological function,and derivatives thereof); S-nitrosylated amino acids (including naturaland synthetic amino acids and their stereoisomers and racemic mixturesand derivatives thereof); S-nitrosylated sugars; S-nitrosylated,modified and unmodified, oligonucleotides (preferably of at least 5, andmore preferably 5-200 nucleotides); straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedS-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.S-nitrosothiols and methods for preparing them are described in U.S.Pat. Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. Proc. Int., 15(3):165-198 (1983), the disclosures of eachof which are incorporated by reference herein in their entirety.

[1775] Another embodiment of the present invention is S-nitroso aminoacids where the nitroso group is linked to a sulfur group of asulfur-containing amino acid or derivative thereof. Such compoundsinclude, for example, S-nitroso-N-acetylcysteine, S-nitroso-captopril,S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine,S-nitroso-cysteine, S-nitroso-glutathione, S-nitroso-cysteinyl-glycine,and the like.

[1776] Suitable S-nitrosylated proteins include thiol-containingproteins (where the NO group is attached to one or more sulfur groups onan amino acid or amino acid derivative thereof) from various functionalclasses including enzymes, such as tissue-type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins; hemeproteins, such as hemoglobin and serum albumin; and biologicallyprotective proteins, such as immunoglobulins, antibodies and cytokines.Such nitrosylated proteins are described in WO 93/09806, the disclosureof which is incorporated by reference herein in its entirety. Examplesinclude polynitrosylated albumin where one or more thiol or othernucleophilic centers in the protein are modified.

[1777] Other examples of suitable S-nitrosothiols include:

[1778] (i) HS(C(R_(e))(R_(f)))_(mm)SNO;

[1779] (ii) ONS(C(R_(e))(R_(f)))_(mm)R_(e); and

[1780] (iii) H₂N—CH(CO₂H)—(CH₂)_(mm)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂H;

[1781] wherein mm is an integer from 2 to 20; R_(e) and R_(f) are eachindependently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy,an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an alkoxy, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a carbamoyl, aurea, a nitro, —T—Q—, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f)taken together are an oxo, a methanthial, a heterocyclic ring, acycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO₂; and Tis independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o) or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)⁻. M⁺, wherein M⁺ is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group.

[1782] In cases where R_(e) and R_(f) are a heterocyclic ring or takentogether R_(e) and R_(f) are a heterocyclic ring, then R_(i) can be asubstituent on any disubstituted nitrogen contained within the radicalwherein R_(i) is as defined herein.

[1783] Nitrosothiols can be prepared by various methods of synthesis. Ingeneral, the thiol precursor is prepared first, then converted to theS-nitrosothiol derivative by nitrosation of the thiol group with NaNO₂under acidic conditions (pH is about 2.5) which yields the S-nitrosoderivative. Acids which can be used for this purpose include aqueoussulfuric, acetic and hydrochloric acids. The thiol precursor can also benitrosylated by reaction with an organic nitrite such as tert-butylnitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate inan inert solvent.

[1784] Another group of NO adducts for use in the present invention,where the NO adduct is a compound that donates, transfers or releasesnitric oxide, include compounds comprising at least one ON—O-, ON—N- orON—C-group. The compounds that include at least one ON—O-, ON—N- orON—C-group are preferably ON—O-, ON—N- or ON—C-polypeptides (the term“polypeptide” includes proteins and polyamino acids that do not possessan ascertained biological function, and derivatives thereof); ON—O-,ON—N- or ON—C-amino acids (including natural and synthetic amino acidsand their stereoisomers and racemic mixtures); ON—O-, ON—N- orON—C-sugars; ON—O-, ON—N- or ON—C-modified or unmodifiedoligonucleotides (comprising at least 5 nucleotides, preferably 5-200nucleotides); ON—O-, ON—N- or ON—C-straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and ON—O-, ON—N- or ON—C-heterocyclic compounds.

[1785] Another group of NO adducts for use in the present inventioninclude nitrates that donate, transfer or release nitric oxide, such ascompounds comprising at least one O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-group.Preferred among these compounds are O₂N13 O-, O₂N—N-, O₂N—S- orO₂N—C-polypeptides (the term “polypeptide” includes proteins and alsopolyamino acids that do not possess an ascertained biological function,and derivatives thereof); O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-amino acids(including natural and synthetic amino acids and their stereoisomers andracemic mixtures); O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-sugars; O₂N—O-,O₂N—N-, O₂N—S- or O₂N—C-modified and unmodified oligonucleotides(comprising at least 5 nucleotides, preferably 5-200 nucleotides);O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedhydrocarbons; and O₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-heterocycliccompounds. Preferred examples of compounds comprising at least oneO₂N—O-, O₂N—N-, O₂N—S- or O₂N—C-group include isosorbide dinitrate,isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitolhexanitrate, nitroglycerin, pentaerythritoltetranitrate andpentrinitrol. Preferred are those —S—NO₂ compounds that are polypeptidesor hydrocarbons with a pair or pairs of thiols that are sufficientlystructurally proximate, i.e., vicinal, that the pair of thiols will bereduced to a disulfide. Compounds which form disulfide species releasenitroxyl ion (NO−) and uncharged nitric oxide (NO.). Compounds where thethiol groups are not sufficiently close to form disulfide bridgesgenerally provide nitric oxide as the NO− form and not as the unchargedNO. form.

[1786] Another group of NO adducts are N-oxo-N-nitrosoamines thatdonate, transfer or release nitric oxide and are represented by theformula: R¹R²N—N(O—M⁺)—NO, where R¹ and R² are each independently apolypeptide, an amino acid, a sugar, a modified or unmodifiedoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and where M⁺ is an organic or inorganic cation, suchas, for example, an alkyl substituted ammonium cation or a Group I metalcation.

[1787] The present invention is also directed to compounds thatstimulate endogenous NO or elevate levels of endogenousendothelium-derived relaxing factor (EDRF) in vivo or are substrates fornitric oxide synthase. Such compounds include, for example, L-arginine,L-homoargrnine, and N-hydroxy-L-arginine, including their nitrosated andnitrosylated analogs (e.g., nitrosated L-arginine, nitrosylatedL-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylatedL-homoarginine), precursors of L-arginine and/or physiologicallyacceptable salts thereof, including, for example, citrulline, omithineor glutamine, inhibitors of the enzyme arginase (e.g.,N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and thesubstrates for nitric oxide synthase, cytokines, adenosine, bradykinin,calreticulin, bisacodyl, and phenolphthalein. EDRF is a vascularrelaxing factor secreted by the endothelium, and has been identified asnitric oxide (NO) or a closely related derivative thereof (Palmer et al,Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA,84:9265-9269 (1987)).

[1788] Another embodiment of the present invention provides compositionscomprising at least one parent COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The parent COX-2 inhibitors includes any of those described inthe prior art, including those described in the patents and publicationscited herein, as well as the novel compounds described herein.

[1789] The present invention is also based on the discovery thatcompounds and compositions of the present invention may also be used inconjunction with other therapeutic agents for co-therapies, partially orcompletely, in place of other conventional antiinflammatory compounds,such as, for example, together with steroids, NSAIDs, 5-lipoxygenase(5-LO) inhibitors, leukotriene B₄ (LTB₄) receptor antagonists,leukotriene A₄ (LTA₄) hydrolase inhibitors, 5-HT agonists, HMG-CoAinhibitors, H₂ receptor antagonists, antineoplastic agents, antiplateletagents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and mixtures thereof.

[1790] Leukotriene A₄ (LTA₄) hydrolase inhibitors refers to compoundsthat selectively inhibit leukotriene A₄ hydrolase with an IC₅₀ of lessthan about 10 μM, and more preferably with an IC₅₀ of less than about 1μM. Suitable LTA₄ hydrolase inhibitors include, but are not limited to,RP-64966, (S,S)-3-amino-4-(4-benzyloxyphenyl)-2-hydroxybutyric acidbenzyl ester (Scripps Res. Inst.),N—(2(R)-(cyclohexylmethyl)-3-(hydroxycarbamoyl)propionyl)-L-alanine(Searle), 7-(4-(4-ureidobenzyl)phenyl) heptanoic acid (Rhone-PoulencRorer), and 3(3-(1E,3E-tetradecadienyl)-2-oxiranyl)benzoic acid lithiumsalt (Searle), and mixtures thereof.

[1791] Suitable LTB₄ receptor antagonists include, but are not limitedto, ebselen, linazolast, ontazolast; WAY 121006 (American HomeProducts); Bay-x-1005 (Bayer); BI-RM-270 (Boehringer Ingleheim);CGS-25019C (Ciba Geigy); ETH-615 (Leo Denmark); MAFP (Merck); TMK-688(Terumo); T-0757 (Tanabe); LY 213024, LY 210073, LY 223982, LY 233469,LY 255283, LY 264086, LY 292728 and LY 293111 (Eli Lilly); ONO-LB457,ONO-4057, and ONO-LB-448 (ONO), S-2474, calcitrol (Shionogi); PF 10042(Perdu Frederick); Pfizer 105696 (Pfizer Inc.); RP 66153(Rhone-Poulenc); SC-53228, SC-41930, SC-50605, SC-51146 and SC-53228(Searle); SB-201146 and SB-209247 (SmithKline Beecham); SKF-104493(SmithKline & French); SM 15178 (Sumitamo); TMK-688 (Terumo); BPC 15,(Warner Lambert); and mixtures thereof. The preferred LTB₄ receptorantagonists are calcitrol, ebselen, Bay-x-1005, CGS-25019C, ETH-615,LY-293111, ONO-4057 and TMK-688, and mixtures thereof.

[1792] Suitable 5-LO inhibitors include, but are not limited to,A-76745, 78773 and ABT761 (Abbott compounds); Bay-x-1005 (Bayer);CMI-392 (Cytomed); E-3040 (Eisai); EF-40 (Scotia Pharmaceutical); F-1322(Fujirebio); ML-3000 (Merckle); PF-5901 (Purdue Frederick); R-840 (3MPharmaceuticals); rilopirox, flobufen, linasolast, lonapolene,masoprocol, ontasolast, tenidap, zileuton, pranlukast, tepoxalin,rilopirox, flezelastine hydrochloride, enazadrem phosphate, andbunaprolast, and mixtures thereof. Suitable 5-LO inhibitors are alsodescribed more fully in WO 97/29776 assigned to G. D. Searle & Co.

[1793] Suitable 5-HT agonists, include, but are not limited to,rizatriptan, sumatriptan, naratriptan, zolmitroptan, eleptriptan,almotriptan, ergot alkaloids. ALX 1323, Merck L 741604 SB 220453 and LAS31416. Suitable 5-HT agonists are described more fully in WO 0025779,assigned to Merck & Co., Inc and in WO 00/48583, assigned to Pozen Inc.5-HT agonists refers to a compound that is an agonist to any 5-HTreceptor, including but not limited to, 5-HT₁ agonists, 5-HT_(1B)agonists and 5-HT_(1D) agonists.

[1794] Suitable steroids, include, but are not limited to, budesonide,dexamethasone, corticosterone, prednisolone, and the like. Suitablesteroids are described more fully in the literature, such as in theMerck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.

[1795] Suitable HMG CoA inhibitors, include, but are not limited to,reductase and synthase inhibitors, such as, for example, squalenesynthetase inhibitors, benzodiazepine squalene synthase inhibitors,squalene epoxidase inhibitors, acyl-coenzyme A, bile acid sequestrants,cholesterol absorption inhibitors, and the like.

[1796] Suitable NSAIDs, include, but are not limited to, acetaminophen,aspirin, diclofenac, ibuprofen, ketoprofen, naproxen and the like.Suitable NSAIDs are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 617-657; and the Merck Index onCD-ROM, Twelfth Edition, Version 12:1, 1996.

[1797] Suitable H₂ receptor antagonists, include, but are not limitedto, cimetidine, roxatidine, rantidine and the like. Suitable H₂ receptorantagonists are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1995, Pgs. 901-915; and the Merck Index onCD-ROM, Twelfth Edition, Version 12:1, 1996.

[1798] Suitable antineoplastic agents, include but are not limited to,5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, altretamine,anaxirone, aclarubicin and the like. Suitable antineoplastic agents arealso described more fully in U.S. Pat. No. 6,025,353 and WO 00/38730assigned to G. D. Searle & Co.

[1799] Suitable antiplatelet agents, include but are not limited to,aspirin, ticlopidine, dipyridamole, clopidogrel, glycoprotein IIb/IIIareceptor antagonists, and the like.

[1800] Suitable decongestants include, but are not limited to,phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,ephinephrine, naphazoline, xylometazoline, propylhexedrine,levo-desoxyephedrine, and the like.

[1801] Suitable antitussives include, but are not limited to, codeine,hydrocodone, caramiphen, carbetapentane, dextramethorphan, and the like.

[1802] Suitable proton pump inhibitors, include, but are not limited to,omeprazole, lansoprazole, rabeprazole, pantoprazole, and the like.Suitable proton pump inhibitors are described more fully in theliterature, such as in Goodman and Gilman, The Pharmacological Basis ofTherapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 901-915; and theMerck Index on CD-ROM, Twelfth Edition, Version 12:1, 1996.

[1803] The compounds and compositions of the present invention, may alsobe used in combination therapies with opioids and other analgesics,including, but not limited to, narcotic analgesics, Mu receptorantagonists, Kappa receptor antagonists, non-narcotic (i.e.non-addictive) analgesics, monoamine uptake inhibitors, adenosineregulating agents, cannabinoid derivatives, neurokinin 1 receptorantagonists, Substance P antagonists, neurokinin 1 receptor antagonists,sodium channel blockers, N—methyl-D-aspartate receptor antagonists, andmixtures thereof. Preferred combination therapies would be withmorphine, meperidine, codeine, pentazocine, buprenorphine, butorphanol,dezocine, meptazinol, hydrocodone, oxycodone, methadone, Tramadol ((+)enantiomer), DuP 747, Dynorphine A, Enadoline, RP-60180, HN—11608,E-2078,ICI-204448, acetominophen (paracetamol), propoxyphene,nalbuphine, E-4018, filenadol, mirtentanil, amitriptyline, DuP631,Tramadol ((−) enantiomer), GP-531, acadesine, AKI-1, AKI-2,GP-1683,GP-3269, 4030W92, tramadol racemate, Dynorphine A, E-2078,AXC3742, SNX-111, ADL2-1294, ICI-204448, CT-3, CP-99,994, CP-99,994, andmixtures thereof.

[1804] The compounds and compositions of the present invention can alsobe used in combination with inducible nitric oxide synthase (iNOS)inhibitors. Suitable iNOS inhibitors are disclosed in U.S. Pat. Nos.5,132,453 and 5,273,875, and in WO 97/38977 and WO 99/18960, thedisclosures of each of which are incorporated by reference herein intheir entirety.

[1805] The present invention is also based on the discovery that theadministration of a therapeutically effective amount of the compoundsand compositions described herein is effective for treatinginflammation, pain (both chronic and acute), and fever, such as, forexample, analgesic in the treatment of pain, including, but not limitedto headaches, migraines, postoperative pain, dental pain, muscular pain,and pain resulting from cancer; as an antipyretic for the treatment offever, including but not limited to, rheumatic fever, symptomsassociated with influenza or other viral infections, common cold, lowback and neck pain, dysmenorrhea, headache, toothache, sprains, strains,myositis, neuralgia, synovitis; arthritis, including but not limited torheumatoid arthritis, degenerative joint disease (osteoarthritis),spondyloarthropathies, gouty arthritis, systemic lupus erythematosus andjuvenile arthritis. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor of the present invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitorand at least one compound that donates, transfers or releases nitricoxide, or elevates levels of endogenous EDRF or nitric oxide, or is asubstrate for nitric oxide synthase. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one nitrosated and/or nitrosylated COX-2 inhibitor, and, at leastone therapeutic agent, including but not limited to, steroids,nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO)inhibitors, leukotriene B₄ (LTB₄) receptor antagonists, leukotriene A₄(LTA₄) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) inhibitors, H₂ antagonists, antineoplastic agents,antiplatelet agents, decongestants, diuretics, sedating or non-sedatinganti-histamines, inducible nitric oxide synthase inhibitors, opioids,analgesics, Helicobacter pylori inhibitors, proton pump inhibitors,isoprostane inhibitors, and, optionally, at least one compound thatdonates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. The compounds can be administered separately or in the form ofa composition.

[1806] Another embodiment of the invention provides methods fordecreasing and/or preventing gastrointestinal disorders and improvingthe gastrointestinal properties of the parent COX-2 inhibitor (i.e.,non-nitrosated and/or non-nitrosylated COX-2 inhibitor) by administeringto the patient in need thereof a therapeutically effective amount of thecompounds and/or compositions described herein. Such gastrointestinaldisorders refer to any disease or disorder of the upper gastrointestinaltract (e.g., esophagus, stomach, duodenum and jejunum) including, forexample, inflammatory bowel disease, Crohn's disease, gastritis,irritable bowel syndrome, ulcerative colitis, peptic ulcers, stressulcers, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, bacterialinfections (including, for example, a Helicobacter Pylori associateddisease), short-bowel (anastomosis) syndrome, hypersecretory statesassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia, and bleeding peptic ulcers that result, for example,from neurosurgery, head injury, severe body trauma or burns. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitor ofthe present invention. In another embodiment, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor and at least one therapeutic agent,including but not limited to, steroids, nonsteroidal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, H₂ antagonists, antineoplastic agents, antiplatelet agents,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

[1807] Yet another embodiment of the invention provides methods forfacilitating wound healing (such as, for example, ulcer healing) byadministering to the patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Woundrefers to, and includes, any lesion that is characterized by loss oftissue, and, includes, but is not limited to, ulcers, cuts, burns, andthe like. Ulcers refers to lesions of the upper gastrointestinal tractlining that are characterized by loss of tissue, and, include, but arenot limited to, gastric ulcers, duodenal ulcers, gastritis, and thelike. For example, the patient can be administered a therapeuticallyeffective amount of at least one nitrosated and/or nitrosylated COX-2inhibitor of the present invention. In another embodiment, the patientcan be administered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor and at least one nitricoxide donor. In yet another embodiment, the patient can be administereda therapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor and at least one therapeutic agent, and,optionally, at least one nitric oxide donor. The compounds can beadministered separately or in the form of a composition.

[1808] Another embodiment of the invention provides methods to decreaseor reverse renal and other toxicities (such as, for example, kidneytoxicity) by administering to a patient in need thereof atherapeutically effective amount of the compounds and/or compositionsdescribed herein. For example, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor of the present invention. In anotherembodiment, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitorand at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one nitrosated and/or nitrosylated COX-2 inhibitor and at leastone therapeutic agent, and, optionally, at least one nitric oxide donor.The compounds can be administered separately or in the form of acomposition.

[1809] Another embodiment of the invention provides methods to treat orprevent disorders resulting from elevated levels of COX-2 byadministering to a patient in need thereof a therapeutically effectiveamount of the compounds and/or compositions described herein. Forexample, the patient can be administered a therapeutically effectiveamount of at least one nitrosated and/or nitrosylated COX-2 inhibitor ofthe present invention. In another embodiment, the patient can beadministered a therapeutically effective amount of at least onenitrosated and/or nitrosylated COX-2 inhibitor and at least one compoundthat donates, transfers or releases nitric oxide, or elevates levels ofendogenous EDRF or nitric oxide, or is a substrate for nitric oxidesynthase. In yet another embodiment, the patient can be administered atherapeutically effective amount of at least one nitrosated and/ornitrosylated COX-2 inhibitor and at least one therapeutic agent,including but not limited to, steroids, a nonsteroidal antiinflammatorycompounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B₄(LTB₄) receptor antagonists, leukotriene A₄ (LTA₄) hydrolase inhibitors,5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)inhibitors, H₂ antagonists, antineoplastic agents, antiplatelet agents,decongestants, diuretics, sedating or non-sedating anti-histamines,inducible nitric oxide synthase inhibitors, opioids, analgesics,Helicobacter pylori inhibitors, proton pump inhibitors, isoprostaneinhibitors, and, optionally, at least one compound that donates,transfers or releases nitric oxide, or elevates levels of endogenousEDRF or nitric oxide, or is a substrate for nitric oxide synthase. Thecompounds can be administered separately or in the form of acomposition.

[1810] Disorders resulting from elevated levels of COX-2 (e.g., COX-2mediated disorders) include, but are not limited to, for example,angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis; skin-related conditions, such as, forexample, psoriasis, eczema, surface wounds, burns and dermatitis;post-operative inflammation including from ophthalmic surgery, such as,for example, cataract surgery and refractive surgery, and the like;treatment of neoplasia, such as, for example, brain cancer, bone cancer,epithelial cell-derived neoplasia (epithelial carcinoma), such as, forexample, basal cell carcinoma, adenocarcinoma, gastrointestinal cancer,such as, for example, lip cancer, mouth cancer, esophageal cancer, smallbowel cancer and stomach cancer, colon cancer, liver cancer, bladdercancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer,breast cancer and skin cancer, such as squamus cell and basal cellcancers, prostate cancer, renal cell carcinoma, and other known cancersthat effect epithelial cells throughout the body, benign and canceroustumors, growths, polyps, adenomatous polyps, including, but not limitedto, familial adenomatous polyposis, fibrosis resulting from radiationtherapy, and the like; treatment of inflammatory processes in diseases,such as, for example, vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome,polymyositis, gingivitis, nephritis, hypersensitivity, swellingoccurring after injury, myocardial ischemia, and the like; treatment ofophthalmic diseases and disorders, such as, for example, retinitis,retinopathies, uveitis, ocular photophobia, acute injury to the eyetissue, glaucoma, inflammation of the eye and elevation of intraocularpressure and the like; treatment of pulmonary inflammation, such as, forexample, those associated with viral infections and cystic fibrosis, andthe like; treatment of certain central nervous system disorders, suchas, for example, cortical dementias including Alzheimer's disease,vascular dementia, multi-infarct dementia, pre-senile dementia,alcoholic dementia, senile dementia, and central nervous system damageresulting from stroke, ischemia and trauma, and the like; treatment ofallergic rhinitis, respiratory distress syndrome, endotoxin shocksyndrome, atherosclerosis; treatment of inflammations and/or microbialinfections including, for example, inflammations and/or infections ofthe eyes, ears, nose, throat, and/or skin; treatment and/or preventionof cardiovascular disorders, such as, for example, coronary arterydisease, aneurysm, arteriosclerosis, atherosclerosis, including, but notlimited to, cardiac transplant atherosclerosis, myocardial infarction,ischemia, embolism, stroke, thrombosis, hypertension, venous thrombosis,thromboembolism, thrombotic occlusion and reclusion, restenosis, angina,unstable angina, shock, heart failure, coronary plaque inflammation,bacterial-induced inflammation, such as, for example, Chlamydia-inducedinflammation, viral induced inflammation, inflammation associated withsurgical procedures, such as, for example, vascular grafting, coronaryartery bypass surgery, revascularization procedures, such as, forexample, angioplasty, stent placement, endarterectomy, vascularprocedures involving arteries, veins, capillaries, and the like;treatment and/or prevention of urinary and/or urological disorders, suchas, for example, incontinence and the like; treatment and/or preventionof endothelial dysfunctions, such as, for example, diseases accompanyingthese dysfunctions, endothelial damage from hypercholesterolemia,endothelial damage from hypoxia, endothelial damage from mechanical andchemical noxae, especially during and after drug, and mechanicalreopening of stenosed vessels, for example, following percutaneoustransluminal angiography (PTA) and percuntaneous transluminal coronaryangiography (PTCA), endothelial damage in postinfarction phase,endothelium-mediated reocclusion following bypass surgery, blood supplydisturbances in peripheral arteries, as well as, cardiovasculardiseases, and the like; preservation of organs and tissues, such as, forexample, for organ transplants, and the like; inhibition and/orprevention of activation, adhesion and infiltration of neutrophils atthe site of inflammation; inhibition and/or prevention of plateletaggregation. The compounds and compositions of the present invention canalso be used as a pre-anesthetic medication in emergency operations toreduce the danger of aspiration of acidic gastric contents.

[1811] When administered in vivo, the compounds and compositions of thepresent invention can be administered in combination withpharmaceutically acceptable carriers and in dosages described herein.When the compounds and compositions of the present invention areadministered as a mixture of at least one nitrosated and/or nitrosylatedCOX-2 inhibitor and at least one nitric oxide donor and/or therapeuticagent, they can also be used in combination with one or more additionalcompounds which are known to be effective against the specific diseasestate targeted for treatment. The nitric oxide donors, therapeuticagents and/or other additional compounds can be administeredsimultaneously with, subsequently to, or prior to administration of thenitrosated and/or nitrosylated COX-2 inhibitor.

[1812] Another embodiment of the present invention provides methods fortreating inflammation, pain and fever; for treating and/or improving thegastrointestinal properties of COX-2 inhibitors; for facilitating woundhealing; for treating and/or preventing renal toxicity; and for treatingand/or preventing other cyclooxygenase-2 mediated disorders comprisingadministration of at least one parent COX-2 inhibitor and at least onenitric oxide donor, and, optionally, at least one therapeutic agent. Forexample, the patient can be administered a therapeutically effectiveamount of at least one parent COX-2 inhibitor of the present inventionand at least one nitric oxide donor. In yet another embodiment, thepatient can be administered a therapeutically effective amount of atleast one parent COX-2 inhibitor, at least one nitric oxide donor and atleast one therapeutic agent. The compounds can be administeredseparately or in the form of a composition.

[1813] The compounds and compositions of the present invention can beadministered by any available and effective delivery system including,but not limited to, orally, bucally, parenterally, by inhalation spray,by topical application, by injection, transdermally, or rectally (e.g.,by the use of suppositories) in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. Parenteral includes subcutaneous injections,intravenous, intramuscular, intrasternal injection, or infusiontechniques.

[1814] Transdermal compound administration, which is known to oneskilled in the art, involves the delivery of pharmaceutical compoundsvia percutaneous passage of the compound into the systemic circulationof the patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitate, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application. Thecompositions can also be applied topically using a transdermal system,such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing.

[1815] Solid dosage forms for oral administration can include capsules,tablets, effervescent tablets, chewable tablets, pills, powders,sachets, granules and gels. In such solid dosage forms, the activecompounds can be admixed with at least one inert diluent such assucrose, lactose or starch. Such dosage forms can also comprise, as innormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, effervescent tablets, and pills, the dosage forms can alsocomprise buffering agents. Soft gelatin capsules can be prepared tocontain a mixture of the active compounds or compositions of the presentinvention and vegetable oil. Hard gelatin capsules can contain granulesof the active compound in combination with a solid, pulverulent carriersuch as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives of gelatin. Tablets and pillscan be prepared with enteric coatings.

[1816] Liquid dosage forms for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrups,and elixirs containing inert diluents commonly used in the art, such aswater. Such compositions can also comprise adjuvants, such as wettingagents, emulsifying and suspending agents, and sweetening, flavoring,and perfuming agents.

[1817] Suppositories for vaginal or rectal administration of thecompounds and compositions of the invention, such as for treatingpediatric fever and the like, can be prepared by mixing the compounds orcompositions with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at room temperature butliquid at rectal temperature, such that they will melt in the rectum andrelease the drug.

[1818] Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions can be formulated according to the known artusing suitable dispersing agents, wetting agents and/or suspendingagents. The sterile injectable preparation can also be a sterileinjectable solution or suspension in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that can be used are water,Ringer's solution, and isotonic sodium chloride solution. Sterile fixedoils are also conventionally used as a solvent or suspending medium.

[1819] The compositions of this invention can further includeconventional excipients, i.e., pharmaceutically acceptable organic orinorganic carrier substances suitable for parenteral application whichdo not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include, for example, water, saltsolutions, alcohol, vegetable oils, polyethylene glycols, gelatin,lactose, amylose, magnesium stearate, talc, surfactants, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, and the like. The pharmaceutical preparations canbe sterilized and if desired, mixed with auxiliary agents, e.g.,lubricants, preservatives, stabilizers, wetting agents, emulsifiers,salts for influencing osmotic pressure, buffers, colorings, flavoringand/or aromatic substances and the like which do not deleteriously reactwith the active compounds. For parenteral application, particularlysuitable vehicles consist of solutions, preferably oily or aqueoussolutions, as well as suspensions, emulsions, or implants. Aqueoussuspensions may contain substances which increase the viscosity of thesuspension and include, for example, sodium carboxymethyl cellulose,sorbitol and/or dextran. Optionally, the suspension may also containstabilizers.

[1820] The composition, if desired, can also contain minor amounts ofwetting agents, emulsifying agents and/or pH buffering agents. Thecomposition can be a liquid solution, suspension, emulsion, tablet,pill, capsule, sustained release formulation, or powder. The compositioncan be formulated as a suppository, with traditional binders andcarriers such as triglycerides. Oral formulations can include standardcarriers such as pharmaceutical grades of mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,and the like.

[1821] Various delivery systems are known and can be used to administerthe compounds or compositions of the present invention, including, forexample, encapsulation in liposomes, microbubbles, emulsions,microparticles, microcapsules and the like. The required dosage can beadministered as a single unit or in a sustained release form.

[1822] The bioavailability of the compositions can be enhanced bymicronization of the formulations using conventional techniques such asgrinding, milling, spray drying and the like in the presence of suitableexcipients or agents such as phospholipids or surfactants.

[1823] The preferred methods of administration of the nitrosated and/ornitrosylated COX-2 inhibitor compositions or the parent COX-2 inhibitorfor the treatment of gastrointestinal disorders are orally, bucally orby inhalation. The preferred methods of administration for the treatmentof inflammation and microbial infections are orally, bucally, topically,transdermally or by inhalation.

[1824] The compounds and compositions of the present invention can beformulated as pharmaceutically acceptable salt forms. Pharmaceuticallyacceptable salts include, for example, alkali metal salts and additionsalts of free acids or free bases. The nature of the salt is notcritical, provided that it is pharmaceutically-acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesuifonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitablepharmaceutically-acceptable base addition salts include, but are notlimited to, metallic salts made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromprimary, secondary and tertiary amines, cyclic amines,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine and thelike. All of these salts may be prepared by conventional means from thecorresponding compound by reacting, for example, the appropriate acid orbase with the compound.

[1825] While individual needs may vary, determination of optimal rangesfor effective amounts of the compounds and/or compositions is within theskill of the art. Generally, the dosage required to provide an effectiveamount of the compounds and compositions, which can be adjusted by oneof ordinary skill in the art, will vary depending on the age, health,physical condition, sex, diet, weight, extent of the dysfunction of therecipient, frequency of treatment and the nature and scope of thedysfunction or disease, medical condition of the patient, the route ofadministration, pharmacological considerations such as the activity,efficacy, pharmacokinetic and toxicology profiles of the particularcompound used, whether a drug delivery system is used, and whether thecompound is administered as part of a drug combination.

[1826] The amount of a given nitrosated and/or nitrosylated COX-2inhibitor or the parent COX-2 inhibitor which will be effective in thetreatment of a particular disorder or condition will depend on thenature of the disorder or condition, and can be determined by standardclinical techniques, including reference to Goodman and Gilman, supra;The Physician's Desk Reference, Medical Economics Company, Inc.,Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis,Mo., 1993. The precise dose to be used in the formulation will alsodepend on the route of administration, and the seriousness of thedisease or disorder, and should be decided by the physician and thepatient's circumstances.

[1827] The amount of nitric oxide donor in a pharmaceutical compositioncan be in amounts of about 0.1 to about 10 times the molar equivalent ofthe COX-2 inhibitor. The usual daily doses of nitrosated and/ornitrosylated COX-2 inhibitors are about 0.001 mg to about 140 mg/kg ofbody weight per day, preferably 0.005 mg to 30 mg/kg per day, oralternatively about 0.5 mg to about 7 g per patient per day. Forexample, inflammations may be effectively treated by the administrationof from about 0.01 mg to 50 mg of the compound per kilogram of bodyweight per day, or alternatively about 0.5 mg to about 3.5 g per patientper day. The compounds may be administered on a regimen of up to 6 timesper day, preferably 1 to 4 times per day, and most preferably once perday. Effective doses may be extrapolated from dose-response curvesderived from in vitro or animal model test systems and are in the sameranges or less than as described for the commercially availablecompounds in the Physician's Desk Reference, supra.

[1828] The present invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of the pharmaceutical compounds and/or compositions of thepresent invention, including, at least, one or more of the COX-2inhibitors optionally substituted with at least one NO and/or NO₂ group,described herein and one or more of the NO donors described herein.Associated with such kits can be additional therapeutic agents orcompositions (e.g., steroids, NSAIDs, 5-lipoxygenase (5-LO) inhibitors,leukotriene B₄ (LTB₄) receptor antagonists and leukotriene A₄ (LTA₄)hydrolase inhibitors, 5-HT agonists, HMG-CoA inhibitors, H₂ antagonists,antineoplastic agents, antiplatelet agents, decongestants, diuretics,sedating or non-sedating anti-histamines, inducible nitric oxidesynthase inhibitors, opioids, analgesics, Helicobacter pyloriinhibitors, proton pump inhibitors, isoprostane inhibitors, and thelike), devices for administering the compositions, and notices in theform prescribed by a governmental agency regulating the manufacture, useor sale of pharmaceuticals or biological products which reflectsapproval by the agency of manufacture, use or sale for humans.

EXAMPLES

[1829] The following non-limiting examples further describe and enableone of ordinary skill in the art to make and use the present invention.In each of the examples, flash chromatography was performed on 40 micronsilica gel (Baker).

Example 1

[1830] 4-(5-(4-Chlorophenyl)-3-((nitrooxy)methyl)-3-hydropyrazolyl)benzenesulfonamide.

[1831] 1a. 4-(5-(4-Chlorophenyl)-3-(hydroxymethyl)-3-hydropyrazolyl)benzenesulfonamide.

[1832] This compound was synthesized as described by Penning et al, J.Med. Chem., 40: 1347-1365 (1997), (the disclosure of which isincorporated by reference herein in its entirety), Example 14a. ¹H NMR(300 MHz, CDCl₃) δ 7.87 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 7.33(d, J=8.7 Hz, 2 H), 7.15 (d, J=8.4 Hz, 2H), 6.54 (s, 1H), 4.79 (s, 2H).

[1833] 1b. 4-(5-(4-Chlorophenyl)-3-((nitrooxy)methyl)-3-hydropyrazolyl)benzenesulfonamide.

[1834] To a solution of the product of Example 1a (348 mg, 0.95 mmol) inEtOAc (10 mL) was added over 5 minutes at room temperature a mixture ofHNO₃ (85 μl, fuming 90%) in acetic anhydride (400 μL). The reaction wasstirred for 15 minutes at room temperature. The mixture was poured intoexcess aqueous Na₂CO₃. The aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over Na₂SO₄ and concentrated. Theresidue was chromatographed on silica gel eluting with 2:1 Hex:EtOAc togive 210 mg (54%) of the title compound. ¹H NMR (300 MHz, CDCl₃) δ 7.90(d, J=8.2 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.15(d, J=8.5 Hz, 2H), 6.61 (s, 1H), 5.55 (s, 2H), 4.97 (s, 2H); ¹³C NMR (75MHz, CDCl₃) δ 146.2, 143.8, 142.4, 141.2, 135.4, 130.0, 129.2, 128.2,127.6, 127.5, 125.1, 109.2, 67.8.

Example 2

[1835] 4-(5-((Nitrooxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide.

[1836] 2a.4-(5-(Hydroxymethyl)-3-phenylisoxazol-4-yl)benzenesulfonamide.

[1837] This compound was synthesized as described in patent applicationWO 96/25405, (the disclosure of which is incorporated by referenceherein in its entirety), Example 10 . ¹H NMR (300 MHz, DMSO-d₆) δ 7.80(d, J=8.3 Hz, 2H), 7.32-7.45 (mult, 9H), 5.71 (t, J=5.3 Hz, 1H), 4.52(d, J=4.5 Hz, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 69.5, 160.7, 143.5,132.6, 130.1, 129.8, 128.8, 128.3, 128.2, 126.0, 115.2, 53.3; massspectrum (API-TIS), m/z 331 (MH⁺).

[1838] 2b.4-(5-((Nitrooxy)methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide.

[1839] Concentrated HNO₃ (40 μL, 0.90 mmol) was added to stirredsolution of acetic anhydride (200 μL, 2.1 mmol) in EtOAc (0.3 mL) at 0°C. via a syringe and stirred for 5 minutes at 0° C. The product ofExample 2a (0.1 g, 0.3 mmol) in EtOAc (0.1 mL) was then added andstirred for 5 minutes at 0° C. The resulting mixture was then subjectedto preparative thin layer chromatography (PTLC) eluting with 1:1Hex:EtOAc to give the title compound (65 mg, 57%) as an oil. The oil wasdissolved in CH₂Cl₂ (5 mL) and solvent was evaporated slowly overnightat room temperature to give the title compound as white crystals. mp47-50° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.4 Hz, 2H), 7.30-7.45(mult, 7H), 5.49 (s, 2H), 4.89 (br s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ161.4, 160.5, 142.3, 133.0, 130.4, 130.3, 128.9, 128.4, 127.2, 127.1,119.5, 62.7; mass spectrum (API-TIS), m/z 376 (MH⁺)

Example 3

[1840] 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethyl3-(N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)carbamoyl)propanoatecitrate salt

[1841] 3a. Ethyl 2-(1-methyl-4-piperidylidene)acetate

[1842] A solution of n-BuLi (1.6M in Hex, 58.7 mL, 93.6 mmol) was addedto a stirred solution of triethyl phosphonoacetate (17.5 g, 78.0 mmol)in THF (30 mL) at −78° C. under N₂. The resulting brownish solution wasstirred for 30 min and then a solution of 4-N-methylpiperidone (8.8 g,78.0 mmol) in THF (20 mL) was added. The cold bath was removed and themixture was stirred at room temperature for 2 hours. Water (250 mL) wasadded and the mixture was extracted with EtOAc (3×100 mL). The combinedorganic extracts were dried over Na₂SO₄. The solvent was evaporated toafford the title compound (13.2 g, 92%). ¹H NMR (300 MHz, CDCl₃) δ 5.64(s, 1H), 4.14 (q, J=7.1 Hz, 2H), 3.00 (t, J=5.1 Hz, 10H), 2.32-2.53(mult, 5H), 2.29 (s, 3H), 1.27 (t, J=7.1 Hz, 3H); ¹³C NMR (75 MHz,CDCl₃) δ 1.664, 158.6, 114.2, 59.5, 56.7, 56.1, 45.7, 36.7, 29.3, 14.2.

[1843] 3b. Ethyl 2-(1-methyl-4-(phenylmethylthio)piperidyl)acetate

[1844] The product of Example 3a (13.2 g, 72.01 mmol) andbenzylmercaptan (8.4 mL, 72.01 mmol) in piperidine (35 mL) were heatedat 100° C. for 12 hours and then cooled to room temperature. Water (50mL) was added and the aqueous layer was extracted with EtOAc (3×100 mL).The combined organic layers were dried over Na₂SO₄. The solvent wasevaporated and the residue was purified by chromatography on silica geleluting with 1:9 MeOH:CH₂Cl₂ to afford the title compound (11.7 g, 53%)as a viscous liquid. ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.34 (mult, 5H),4.17(q, J=7.1 Hz, 2H), 3.71 (s, 2H), 2.64 (s, 2H), 2.46-2.54 (mult, 4H),2.29 (s, 3H), 1.83-1.95 (mult, 4H), 1.29 (t, J=7.1 Hz, 3H).

[1845] 3c. 2-(1-Methyl-4-(phenylmethylthio)-4-piperidyl)ethan-1-ol

[1846] A solution of diisobutylaluminium hydride in hexane (83 mL, 83mmol) was added to a stirred solution of the product of Example 3b (11.7g, 38.74 mmol) in THF (40 mL) at −78° C. under N₂. The cold bath wasremoved and the mixture was stirred for 1.5 hours. Solid Na₂SO₄.10H₂O (3g) was added portionwise with stirring until a thick precipitate wasformed. 10% MeOH in CH₂Cl₂ (100 mL) was added and the mixture wasfiltered. The solid was washed with additional 10% MeOH in CH₂Cl₂ (100mL) and the solvent was evaporated. The residue was chromatographed onsilica gel eluting with 1:9 MeOH:CH₂Cl₂ to give the title compound (5.2g, 50.6%) as a solid. ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.35 (mult, 5H),3.86 (t, J=6.4 Hz, 2H), 3.66 (s, 2H), 2.50-2.57 (mult, 4H), 2.29 (s,3H), 1.88 (t, J=6.5 Hz, 2H), 1.65-1.84 (mult, 4H).

[1847] 3d. 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethan-1-ol

[1848] The product of Example 3c (7.8 g, 29.38 mmol) was dissolved inTHF (50 mL) and cooled to −78° C. and liquid NH₃ (˜100 mL) was added.Small pieces of metallic sodium (2 g) were added until the blue colorpersisted for 10 minutes. Solid NH₄Cl (˜5 g) was added to discharge thecolor and the cold bath was removed and ammonia was evaporated (12hours). Ether (100 mL) was added to the pale yellow solid and HCl inEt₂O (10 mL) was added until the solution became acidic. The mixture wasleft in a freezer for 30 min. The solid which formed was removed byfiltration and washed with Et₂O (50 mL). The residue was triturated withMeOH (100 mL) and undissolved solid was removed by filtration. Thesolvent was concentrated to 25 mL and concentrated HCl (2 mL) was added.90% t-BuONO (3.1 mL, 23.7 mmol) was added via syringe. The resultingolive green solution was stirred at room temperature for 20 minutes andthen poured onto crushed ice (5 g). 10% Na₂CO₃ (10 mL) was added and themixture was extracted with EtOAc (3×50 mL). The combined organics weredried over Na₂SO₄ and concentrated to give the title compound (3.6 g,60%) as a green oil. ¹H NMR (300 MHz, CDCl₃) δ 3.88 (t, J=6.9 Hz, 2H),2.25-2.95 (mult, 13H), 2.30 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 62.5,58.5, 57.8, 51.5, 46.1, 36.4.

[1849] 3e. 4-(5-(Methyl)-3-phenylisoxazol-4-yl)benzenesulfonamide.

[1850] This compound was synthesized as described in patent applicationWO 96/25405, Example 1, the disclosure of which is incorporated byreference herein in its entirety. mp 170° C. ¹H NMR (300 MHz, CD₃CN) δ7.90 (d, J=8.4 Hz, 2 H), 7.39-7.49 (mult, 7 H), 5.48 (s, 2 H), 2.50 (s,2 H); mass spectrum (API-TIS), m/z 315 (MH⁺).

[1851] 3f. 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethyl3-(N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)carbamoyl)propanoate.

[1852] To a stirred solution of the product of Example 3d (0.21 g, 1.03mmol), the product of Example 3e (0.43 g, 1.03 mmol), and4-(dimethylamino)pyridine (DMAP, 0.05 g) in CH₂Cl₂ (10 mL) was addedsolid DCC (0.34 g, 164 mmol). The solution was stirred for 24 hours atroom temperature. The precipitate which formed was removed by filtrationand the filtrate was concentrated under reduced pressure. The crudeproduct was chromatographed on silica gel eluting with 1:1 EtOAc:Hexfollowed by 1:9 MeOH:CH₂Cl₂. This gave the title compound (178 mg, 29%)as a green foam. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d, J=8.2 Hz, 2H),7.22-7.39 (mult, 7H), 4.47-4.57 (mult, 2H), 3.56-3.60 (mult, 2H),3.15-3.25 (mult, 2H), 2.45-2.90 (mult, 10OH), 2.42 (s, 6H); ¹³C-NMR (75MHz, CDCl₃) δ 178.5, 173.4, 167.1, 161.0, 143.0, 133.5, 129.7, 129.5,128.6, 128.5, 128.4, 126.7, 114.9, 60.0, 56.2, 51.7, 45.5, 41.0, 33.9,31.8, 30.3, 11.6; mass spectrum (API-TIS), m/z 601 (MH⁺).

[1853] 3g. 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethyl3-(N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)carbamoyl)propanoate Citrate Salt.

[1854] Citric acid (65 mg, 0.34 mmol) in MeOH (0.2 mL) was added to theproduct of Example 3f (170 mg, 0.28 mmol) dissolved in EtOAc (0.8 mL)and MeOH (0.4 mL). The green solution was left to crystallize at −20° C.for 48 hours. The solvent was decanted and the solid was dried underreduced pressure for 16 hours to give the title compound (124 mg, 55%)as shiny, olive green crystals. mp 82-84° C. (decom). ¹H-NMR (300 MHz,CDCl₃) δ 8.16 (d, J=8.4 Hz, 2H), 7.52-7.60 (mult, 7H), 4.43 (t, J=6.4Hz, 2H), 3.15-3.25 (mult, 2H), 2.50-2.99 (mult, 22H); mass spectrum(API-TIS), m/z 601 (MH⁺).

Example 4

[1855](2-(1-((4-Chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl)ethyl)nitrooxy

[1856] 4a.2-(1-((4-Chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl)ethan-1-ol

[1857] A solution of indomethacin (10 g, 28 mmol) in THF (90 mL) wasimmersed in an ice bath to maintain an internal temperature of 10-15° C.To this solution was added BF₃-Et₂O (30 mL, 230 mmol) over 5 min,resulting in the formation of a precipitate. Sodium borohydride (4.2 g,110 mmol) was added portionwise over 10 min resulting in vigorouseffervescence. After gas evolution subsided the flask was stoppered andallowed to warm to room temperature. After 1 hour the pressure wasvented through a needle. The heterogeneous mixture was stirred for 6hours. The mixture was cooled in an ice bath and was quenched by addingsaturated NaHCO₃. To break the resultant emulsion the mixture was madeacidic with 1N HCl and extracted with a 3:1 mixture of Et₂O:Hexane (270mL). The organic layer was washed with brine, dried over Na₂SO₄, andevaporated. The residue was taken up in a 3:1 mixture of hot Hex:EtOAc(80 mL). Upon cooling to room temperature, crystals began to form.Crystallization was completed by cooling to −20° C. The solid wasremoved by filtration, washed with cold 3:1 Hex:EtOAc (2×25), Hexane(1×25) and dried in vacuo. This gave the title compound (4.5 g, 49%) asa white solid. mp 113-115° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.24 (d, J=8.4Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 7.03 (d, J=3.5 Hz, 1H), 6.87 (d, J=8.3Hz, 2H), 6.78 (dd, J=2.4 and 8.7 Hz, 1H), 5.23 (s, 2H), 3.86 (s, 3H),3.84 (t, J=6.5 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.29 (s, 3H); massspectrum (API-TIS) m/z 330 (MH+). Anal calcd for C₁₉H₂₀ClNO₂: C, 69.19;H, 6.11; N, 4.25; Cl, 10.75. Found: C, 68.98; H, 6.30; N, 4.08; Cl,10.60.

[1858] 4b.3-(2-Bromoethyl)-1-((4-chlorophenyl)methyl)-5-methoxy-2-methylindole

[1859] To the product of Example 4a (160 mg, 0.5 mmol) in toluene (1 mL)was added PBr₃ (17 μL, 0.18 mmol). The reaction mixture was heated to100° C. for 10 min then cooled to room temperature. The mixture waspartitioned between EtOAc and 1N HCl. The aqueous layer was extractedwith EtOAc (1×10). The combined organic layers were washed with H₂O(1×10), brine (2×10), dried over Na₂SO₄, and evaporated. This gave thetitle compound (170 mg, 87%) which solidified on standing. This materialwas used in the next reaction without further purification. ¹H-NMR (300MHz, CDCl₃) δ 7.24 (d, J=8.4 Hz, 2H), 7.06 (d, J=9.1 Hz, 1H), 6.99 (d,J=2.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.78 (dd, J=2.4 and 8.8 Hz, 1H),5.23 (s, 2H), 3.87 (s, 3H), 3.56 (t, J=7.5 Hz, 2H), 3.28 (t, J=7.5 Hz,2H), 2.29 (s, 3H).

[1860] 4c.(2-(1-((4-Chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl)ethyl)nitrooxy

[1861] The product of Example 4b (170 mg, 0.43 mmol) was dissolved inCH₃CN (6 mL). Addition of AgNO₃ (85 mg, 0.5 mmol) caused immediateformation of a precipitate. After 20 min, the reaction mixture wasfiltered through Celite and concentrated. The residue was purified bychromatography on silica gel eluting with 5:1 Hex:EtOAc. This gave thetitle compound (90 mg, 56%) as a white crystalline solid. mp 94-95° C.¹H-NMR (300 MHz, CDCl₃) δ 7.23 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.9 Hz,1H), 6.99 (d, J=2.4 Hz, 1H), 6.86 (d, J=8.4 Hz, 2H), 6.79 (dd, J=2.4 and8.4 Hz, 1H), 5.23 (s, 2H), 4.60 (t, J=7.2 Hz, 2H), 3.87 (s, 3H), 3.14(t, J=7.3 Hz, 2H), 2.28 (s, 3H); mass spectrum (API-TIS): m/z 375 (MH⁺).Anal calcd for C₁₉H₁₉ClN₂O₄: C, 60.88; H, 5.11; N, 7.47; Cl, 9.46.Found: C, 60.89; H, 5.23; N, 7.36; Cl, 9.58.

Example 5

[1862]1-(3-(4-Fluorophenyl)-7-(nitrooxymethyl)(3a-hydroimidazolo(1,2-a)pyridin-2-yl))-4-(methylsulfonyl)benzene

[1863] 5a.1-(3-(4-Fluorophenyl)-7-(hydroxymethyl)(3a-hydroimidazolo(1,2-a)pyridin-2-yl))-4-(methylsulfonyl)benzene

[1864] This compound was prepared according to a procedure described inpatent application WO 96/31509, (the disclosure of which is incorporatedby reference herein in its entirety), Example 15. ¹H-NMR (300 MHz,CDCl₃) δ 7.80-7.87 (m, 5H), 7.40-7.46 (m, 2H), 7.20-7.33 (m, 3H),6.82-6.86 (t, 2H, J=7.0 Hz), 5.11 (s, 2H), 3.04 (s, 3H; mass spectrum(API-TIS) m/z 397 (MH⁺).

[1865] 5b.1-(3-(4-Fluorophenyl)-7-(nitrooxymethyl)(3a-hydroimidazolo(1,2-a)pyridin-2-yl))-4-(methylsulfonyl)benzene

[1866] A suspension of the product of Example 5a (210 mg, 0.52 mmol) wasadded to an ice-cold mixture of acetic anhydride (393 μL, 4.16 mmol) andnitric acid (110 μL, 2.61 mmol). The resulting mixture was allowed towarm up to 10° C. and stirred for 1 hour. The mixture was then dilutedwith methylene chloride, washed with cold saturated sodium bicarbonatesolution and brine, dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was suspended in hexane/ethyl acetate (2:1)mixture and filtered to give 230 mg (99% yield) of the title compound asa yellow-orange solid. m.p. 145-147° C. ¹H-NMR (300 MHz, CDCl₃) δ8.07-8.12 (d, 1 H, J=7.0 Hz), 7.82-7.56 (m, 4 H), 7.48-7.56 (m, 2 H),7.32-7.39 (m, 2 H), 6.95-7.01 (t, 1 H, J=7.0 Hz), 5.96 (s, 2 H), 3.12(s, 3 H).

Example 6

[1867] Ethyl6-chloro-8-((nitrooxy)methyl)-2-(trifluoromethyl)-2H-chromene-3carboxylate

[1868] 6a. Ethyl 6-chloro-8-formyl-2-(trifluoromethyl)-2H-chromene-3carboxylate

[1869] This compound was synthesized as described in patent applicationWO 98/47890, (the disclosure of which is incorporated by referenceherein in its entirety), Example 76. ¹H-NMR (300 MHz, CDCl₃) δ 10.39 (s,1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.40 (s, 1H), 5.86 (q, J=6.6 Hz, 1H),4.31-4.44 (mult, 2H), 1.37 (t, J=7.1 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ186.3, 163.0, 153.5, 134.4, 134.1, 130.1, 128.4, 125.0, 124.8, 121.8,121.0, 119.2, 71.1 (q, J_(C-F)=134 Hz), 62.0, 14.1.

[1870] 6b. Ethyl6-chloro-8-(hydroxymethyl)-2-(trifluoromethyl)-2H-chromene-3 carboxylate

[1871] Na(OAc)₃BH (2.4 g, 11.2 mmol) was added to a stirred solution ofthe product of Example 6a (1.5 g, 4.5 mmol) in CH₂Cl₂ (50 mL) and theresulting solution was stirred at room temperature for 3 days. Thesolution was poured into water (100 mL), the CH₂Cl₂ layer was separatedand the aqueous layer was extracted with CH₂Cl₂ (2×25 mL). The combinedorganic layers were dried over Na₂SO₄. The solvent was evaporated underreduced pressure and the crude material was chromatographed on silicagel eluting with EtOAc:Hexane (1:5) to give the title compound (1.2 g,79%) as a white solid. mp 98-100° C. ¹H-NMR (300 MHz, CDCl₃) 7.66 (s,1H), 7.41 (d, J=2.3 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 5.76 (q, J=6.7 Hz,1H), 4.71 (d, J=5.5 Hz, 2H), 4.26-4.70 (mult, 2H), 2.06-2.10 (br mult,1H), 1.15-1.21 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.4, 146.7,135.7, 131.2, 130.3, 127.7, 127.6, 121.3, 120.1, 118.0, 70.6 (q,J_(C-F)=133 Hz), 61.7, 59.6, 14.1; mass spectrum (API-TIS) m/z 354(M+NH₄ ⁺). Anal. Calcd for C₁₄H₁₂ClF₃O₄: C, 49.94; H, 3.59; F, 16.93;Cl, 10.53. Found: C, 49.83; H, 3.52; F, 17.10; Cl, 10.77.

[1872] 6c. Ethyl6-chloro-8-((nitrooxy)methyl)-2-(trifluoromethyl)-2H-chromene-3carboxylate

[1873] Fuming HNO₃ (340 μL, 3.6 mmol) was added to a stirred solution ofacetic anhydride (1.12 mL, 11.8 mmol) in EtOAc (10 mL) at 0° C. viasyringe. The mixture was allowed to stir for 5 min at 0° C. The productof Example 6b. (0.5 g, 1.49 mmol) in EtOAc (10 mL) was then added andstirred for 15 min at 0° C. The reaction mixture was poured into icecold saturated NaHCO₃ (25 mL) and shaken well. The organic layer wasseparated and dried over Na₂SO₄. The solvent was evaporated underreduced pressure to afford a viscous oil which was dissolved in hexane(15 mL). The resulting solution was left in a freezer at −20° C. for 12hours to give the title compound (0.44 g, 77%). mp 53° C. ¹H-NMR (300MHz, CDCl₃) δ 7.65 (s, 1H), 7.34 (d, J=2.4 Hz, 1H), 7.25 (d, J=2.4 Hz,1H), 5.78 (q, J=6.6 Hz, 1H), 5.46 (s, 2H), 4.28-4.38 (mult, 3H), 1.35(t, J=7.1 Hz, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.0, 150.0, 135.0, 133.0,130.0, 127.6, 125.0, 121.8, 121.1, 120.8, 118.8, 71.3 (q, J_(C-F)=133Hz), 68.0, 61.8, 14; mass spectrum (API-TIS) m/z 399 (M+NH₄ ⁺). Anal.Calcd for C₁₄H₁₁ClF₃O₆: C, 44.06; H, 2.90; F, 14.93; Cl, 9.29; N, 3.67.Found: C, 44.00; H, 2.85; F, 14.83; Cl, 9.14; N, 3.57.

Example 7

[1874]2-(1-((4-Chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)-N-(2-methyl-2-(nitrosothio)propyl)acetamide

[1875] 7a.2-(1-((4-Chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)-N-(2-methyl-2-sulfanylpropyl)acetamide

[1876] A solution of indomethacin (3.6 g, 10 mmol) and Et₃N (1.5 mL, 11mmol) in THF (50 mL) was cooled to 0° C. i-Butyl chloroformate (1.5 mL,11 mmol) was added dropwise and the reaction was allowed to stir for 20min. To the resulting solution was added a slurry of1-amino-2-methyl-2-propanethio.HCl (1.4 g, 10 mmol) and Et₃N (1.5 mL, 11mmol) in DMF (20 mL). The reaction mixture was kept cold for 2 hours,warmed to room temperature and stirred for 1 hour. The mixture waspartitioned between Et₂O and dilute HCl. The organic layer was separatedand washed with saturated NaHCO₃, brine, filtered and dried over Na₂SO₄.Evaporation of the solvent gave a residue which was recrystallized fromEtOAc to give the title compound (1.1 g, 25%) as a white solid. mp177-178° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.67 (d, J=8.5 Hz, 2H), 7.48 (d,J=8.4 Hz, 2H), 6.92 (d, J=2.3 Hz, 1H), 6.91 (d, J=9.0 Hz, 1H), 6.71 (dd,J=2.5 and 9.1 Hz, 1H), 6.10 (br t, J=6.3 Hz, 1H), 3.83 (s, 3H), 3.69 (s,2H), 3.27 (d, J=6.3 Hz, 2H), 2.42 (s, 3H), 1.36 (s, 1H), 1.26 (s, 6H);mass spectrum (API-TIS) m/z 445(447) MH⁺ (1-Cl).

[1877] 7b.2-(1-((4-Chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl)-N-(2-methyl-2-(nitrosothio)propyl)acetamide

[1878] The product of Example 7a (25 mg, 0.056 mmol) was dissolved inCH₂Cl₂ (1 mL) and cooled to 0° C. A solution of t-BuONO (7.5 μL, 0.056mmol) in CH₂Cl₂ was added dropwise. The reaction mixture was allowed towarm to room temperature with stirring for 30 min. Evaporation of thesolvent gave the title compound (25 mg, 100%) as a green crystallinesolid. mp 122-125° C. dec. ¹H-NMR (300 MHz, CDCl₃) δ 7.64 (d, J=8.5 Hz,2H), 7.51 (d, J=8.4 Hz, 2H), 6.84 (d, J=9.1 Hz, 1H), 6.82 (d, J=2.5 Hz,1H), 6.78 (dd, J=2.5 and 9.1 Hz, 1H), 5.96 (br t, J=6.4 Hz, 1H), 3.97(d, J=6.4 Hz, 2H), 3.79 (s, 3H), 3.67 (s, 2H), 2.32 (s, 3H), 1.78 (s,6H); mass spectrum (API-TIS) m/z 491(493) M+NH⁺ (1-Cl).

Example 8

[1879] Ethyl(2Z)-3-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoate

[1880] 8a. Ethyl(2Z)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enoate

[1881] This compound was synthesized as described in U.S. Pat. No.5,807,873, (the disclosure of which is incorporated by reference hereinin its entirety), Example 64. mp 126° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.93(dd, J=1.75 and 8.3 Hz, 2H), 7.46 (dd, J=1.78 and 6.7 Hz, 2H), 7.25-7.30(mult, 2H), 7.04-7.09 (mult, 2H), 4.01 (q, J=7.1 Hz, 2H), 3.76 (t, J=6.2Hz, 2H), 3.09 (s, 3H), 2.62 (t, J=6.1 Hz, 2H), 0.97 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 170.2, 145.6, 144.6, 140.0, 139.5, 134.2,132.7, 130.3, 129.9, 128.5, 127.6, 61.3, 61.1, 44.4,35.0, 13.6; massspectrum (API-TIS) m/z 409 (MH⁺), 426 (MNH₄ ⁺). Anal. Calcd forC₂₀H₂₁ClO₅S: C, 58.75; H, 5.18; Cl, 8.67; S, 7.84. Found: C, 58.64; H,5.02; Cl, 8.80; S, 7.79.

[1882] 8b. Ethyl(2Z)-3-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoate

[1883] A suspension of the product of Example 8a (2.02 g, 4.95 mmol) inCHCl₃ (20 mL) was added dropwise to a mixture of acetic anhydride (3.71mL, 4.04 g, 39.6 mmol) and 90% fuming nitric acid (1.03 mL, 1.56 g, 24.8mmol) at −12° C. The resultant solution was stirred at −12° C. for 1hour. CH₂Cl₂ (30 mL) was added, washed with ice cold saturated NaHCO₃,dried over Na₂SO₄ and filtered. Evaporation of the solvent gave aresidue that was recrystallized from 1:2 Hexane:CH₂Cl₂ to give the titlecompound (1.82 g, 82%) as a white solid. mp 127-128° C. ¹H-NMR (300 MHz,CDCl₃) δ 7.97 (d, J=8.3 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 7.27-7.31(mult, 2H), 7.03-7.08 (mult, 2H), 4.59 (t, J=6.4 Hz, 2H), 4.02 (q, J=7.1Hz, 2H), 3.09 (s, 3H), 2.76 (t, J=6.4 Hz, 2H), 0.98 (t, J=7.1 Hz, 3H);¹³C NMR (75 MHz, CDCl₃) δ 168.8, 147.6, 145.3, 140.5, 139.2, 134.6,129.9, 129.8, 129.4, 128.7, 128.0, 70.8, 61.4, 44.5, 29.9, 13.6; massspectrum (API-TIS) m/z 471 (MNH₄ ⁺). Anal. Calcd for C₂₀H₂₀ClNO₇S: C,52.92; H, 4.44; N, 3.09; Cl, 7.81; S, 7.06. Found: C, 52.91; H, 4.35; N,2.93; Cl, 7.89, S, 7.20.

Example 9

[1884](2Z)-3-(4-Chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoicacid

[1885] 9a.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enoicacid

[1886] NaOH (6.4 mL of 1.5 N, 0.38 g, 9.6 mmol) was added dropwise to asolution of the product of Example 8a (3.62 g, 8.87 mmol) in EtOH (80mL) at 0° C. The resultant pale yellow solution was stirred at roomtemperature for 2 hours. The residue, after evaporation of the solvent,was dissolved in water and washed with EtOAc. Crushed ice was added tothe aqueous layer which was then acidified with 10% HCl to ˜pH=4 andextracted with EtOAc. The organic layer was dried over Na₂SO₄ andfiltered. Evaporation of the solvent gave a residue that wasrecrystallized from EtOAc:Hex:CH₂Cl₂ to give the title compound (2.79 g,82%) as a white solid. mp 144-145° C. ¹H-NMR (300 MHz, CDCl₃/MeOH-d₄) δ7.98 (d, J=7.1 Hz, 2H), 7.53 (d, J=7.0 Hz, 2H), 7.29-7.32 (mult, 2H),7.16-7.19 (mult, 2H), 3.71 (t, J=6.9 Hz, 2H), 3.15 (s, 3H), 2.56 (t,J=6.8 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 173.1, 147.4, 145.1, 141.4,141.2, 134.9, 134.3, 131.4, 131.3, 129.4, 128.7, 61.3, 61.3, 44.3, 36.3;mass spectrum (API-TIS) m/z 363 (M−H₂O), 381 (MH⁺), 398 (MNH₄ ⁺). Anal.Calcd for C₁₈H₁₇ClO₅S: C, 56.77; H, 4.50; Cl, 9.31; S, 8.42. Found: C,56.64; H, 4.44; Cl, 9.40; S, 8.18.

[1887] 9b.(2Z)-3-(4-Chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoic acid

[1888] A suspension of the product of Example 9a (1.37 g, 3.66 mmol) inCHCl₃ (54 mL) was added dropwise to a mixture of acetic anhydride (2.72mL, 2.94 g, 28.8 mmol) and 90% fuming nitric acid (0.76 mL, 1.14 g, 18.0mmol) at −12° C. The resultant solution was stirred at −12° C. for 30min. CH₂Cl₂ (25 mL) was added, washed with water, dried over Na₂SO₄ andfiltered. Evaporation of the solvent gave a residue that wasrecrystallized from EtOAc:Hexane:CH₂Cl₂ to give the title compound (0.9g, 59%) as a white solid. mp 143-144° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.98(d, J=8.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.27-7.32 (mult, 2H),7.07-7.11 (mult, 2H), 4.61 (t, J=6.3 Hz, 2H), 3.10 (s, 3H), 2.78 (t,J=6.3 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ 172.8, 150.9, 145.4, 140.7,138.7, 135.1, 129.8, 129.7, 129.0, 128.1, 127.7, 70.8, 44.5, 30.0; massspectrum (API-TIS) m/z 443 (MNH₄ ⁺). Anal. Calcd for C₁₈H₁₆ClNO₇S: C,50.77; H, 3.79; N, 3.29; Cl, 8.33; S, 7.53. Found: C, 50.87; H, 3.67; N,3.13; Cl, 8.26, S, 7.43.

Example 10

[1889](2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2(nitrosothio)propyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enamide

[1890] 10a.(2Z)-3-(4-Chlorophenyl)-N-(2-methyl-2-sulfanylpropyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(1,1,2,2,-tetramethyl-1-silapropoxy)ethyl)prop-2-enamide

[1891] To a solution of the product of Example 9a (0.5 g, 1.32 mmol) andimidazole (0.18 g, 2.63 mmol) in dry THF (10 mL) was added a solution oft-butyldimethyl-chlorosilane (0.4 g, 2.63 mmol) in dry THF (10 mL)dropwise at room temperature. The resulting white suspension was stirredat room temperature for 16 hours. The reaction mixture was partitionedbetween EtOAc and saturated NaHCO₃. The organic layer was separated,washed with 10% HCl, dried over Na₂SO₄, filtered and concentrated invacuo to give 1:1 mono:disilylated product as a white foam which wasused in the next step without further purification. Mass spectrum(API-TIS) m/z 495 and 609 (MH⁺). The entire white foam was dissolved inTHF (10 mL). Bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.70 g, 1.58mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.32 mmol) were added atroom temperature. After 5 min, 1-amino-2-methyl-2-propanethiol (0.15 g,1.41 mmol) in THF (2 mL) was added dropwise. The resulting pale yellowsolution was stirred at room temperature for 2.5 hours. Evaporation ofthe solvent gave a residue that was chromatographed on silica geleluting with 1:1 EtOAc:Hexane to give the title compound (0.28 g, 37%)as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 7.90 (d, J=8.3 Hz, 2H), 7.56(d, J=8.3 Hz, 2H), 7.29 (d, J=8.4 Hz, 2H), 7.15 (d, J=6.7 Hz, 2H), 5.91(t, J=6.2 Hz, 1H), 3.77 (t, J=5.9 Hz, 2H), 3.15 (d, J=6.2 Hz, 2H), 3.09(s, 3H), 2.64 (t, J=5.9 Hz, 2H), 1.28 (s, 1H), 1.11 (s, 6H), 0.96 (s,9H), 0.09 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 170.2, 145.9, 140.2, 139.8,139.4, 137.9, 134.4, 130.9, 130.6, 129.1, 127.4, 60.6, 60.4, 53.5, 52.7,44.6, 44.5, 35.0, 29.9, 26.1, 21.1, 18.4, 14.3, −5.2; mass spectrum(API-TIS) m/z 582 (MH⁺). Anal. Calcd for C₂₈H₄₀ClNO₄S₂Si: C, 57.76; H,6.92; N, 2.41. Found: C, 57.79; H, 6.67; N, 2.30.

[1892] 10b.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2-sulfanylpropyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enamide

[1893] To a solution of the product of Example 10a (225 mg, 0.39 mmol)in THF (13 mL) was added dropwise trifluoroacetic acid (129 μL, 1.67mmol) at 0° C. To this was added tetrabutylammonium fluoride (385 μL of1M solution in THF, 0.39 mmol) dropwise. The resultant solution wasgradually warmed to room temperature and stirred for 25 hours. Thereaction mixture was partitioned between EtOAc (50 mL) and ice cold 1%HCl. The organic layer was separated, dried over Na₂SO₄ and filtered.The solvent was evaporated and the residue was chromatographed on silicagel eluting with 5% MeOH:CH₂Cl₂ to give the title compound (175 mg, 97%)as a white foam. mp 62-64° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.2Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 7.16 (d, J=8.4Hz, 2H), 6.05 (t, J=6.1 Hz, 1H), 3.72 (t, J=5.7 Hz, 2H), 3.14 (d, J=6.1Hz, 2H), 3.09 (s, 3H), 2.59 (t, J=5.7 Hz, 2H), 1.36 (s, 1H), 1.16 (s,6H), ¹³C NMR (75 MHz, CDCl₃) δ 171.1, 145.8, 141.1, 140.0, 138.8, 137.3,134.7, 130.5, 130.4, 129.2, 127.8, 61.0, 52.9, 44.7, 44.6, 34.9, 30.0;mass spectrum (API-TIS) m/z 468 (MH⁺).

[1894] 10c.(2Z)-3-(4-Chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2-(nitrosothio)propyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enamide

[1895] To a solution of t-butyl nitrite (0.2 mL of 90% solution, 158 mg,1.53 mmol) in 1:1 MeOH:CH₂Cl₂ (1.2 mL) was added dropwise a solution ofthe product of Example 10b (156 mg, 0.33 mmol) in 1:1 MeOH:CH₂Cl₂ (2 mL)at 0° C. The resultant solution was stirred at 0° C. in the dark for 30min. Additional-t-butyl nitrite (0.15 mL of 90% solution, 118 mg, 1.15mmol) was added and the resultant green solution was stirred at 0° C.for a further 30 min and then at room temperature for 20 min. Thevolatiles were removed in vacuo and the residue was chromatographed onsilica gel eluting with 1:1 EtOAc:CH₂Cl₂ to give the title compound (96mg, 58%) as a green solid. mp 150-153° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.90(d, J=8.3 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.24 (dd, J=1.9 and 6.6 Hz,2H), 7.09-7.12 (mult, 2H), 6.40 (br t, J=6.3 Hz, 1H), 3.86 (J=6.3 Hz,2H), 3.66 (t, J=5.9 Hz, 2H), 3.09 (s, 3H), 2.54 (t, J=5.8 Hz, 2H), 1.67(s, 6H), ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 145.8, 141.2, 139.8, 138.8,136.9, 134.5, 130.5, 130.3, 129.0, 127.6, 60.5, 56.5, 44.5, 34.7, 26.8;mass spectrum (API-TIS) m/z 467 (M−NO), 497 (MH⁺).

Example 11

[1896]1-(5-methyl-1-(2-methyl-2-(nitrosothio)propyl)pyrrol-2-yl)-4-(methylsulfonyl)benzene

[1897] 11a. 1-(4-Methylthiophenyl)pentane-1,4-dione

[1898] 4-(Methylthio)benzaldehyde (20 mL, 150 mmol),3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride (7 g, 30 mmol),methyl vinyl ketone (15 mL, 180 mmol), and Et₃N (21 mL, 150 mmol) wereplaced in a flask and immersed in an oil bath at 80° C. The initialpurple colored solution became orange over 30 min. The solution wascooled to room temperature, EtOAc (30 mL) was added to precipitate thethiazolium salt which was removed by filtration. The filter cake waswashed with hot EtOAc (2×30 mL). The combined mother liquor and washeswere concentrated to give 43 g of residue. The residue was taken up inhot 1:1 Hexane:EtOAc (100 mL), which upon cooling deposited a solid.This solid was isolated on a glass frit and washed with hot 4:1Hexane:EtOAc (50 mL). From this hot wash was deposited the titlecompound (16.4 g, 49%) as a tan solid. mp 72-73° C. ¹H-NMR (300 MHz,CDCl₃) δ 7.88 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H), 3.22 (t, J=6.5Hz, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.51 (s, 3H), 2.24 (s, 3H); massspectrum (API-TIS) m/z 223 (MH⁺). Anal. Calcd. for C₁₂H₁₄O₂S: C, 64.84;H, 6.35; S, 14.42. Found C, 64.68; H, 6.19; S, 14.24.

[1899] 11b. 1-(4-(Methylsulphonyl)phenyl)pentane-1,4-dione

[1900] The product of Example 11a (16.4 g, 74 mmol) was dissolved inCH₂Cl₂ (300 mL) and cooled to 0° C. Solid 70% m-chloroperbenzoic acid(37 g, 150 mmol) was added portionwise over 5 min. After completeaddition the cold bath was removed and the reaction mixture was allowedto warm to room temperature with stirring for 3 hours. The precipitatethat had formed was removed by filtration and washed with CH₂Cl₂ (2×50mL). The combined organic filtrates were washed with 1M Na₂CO₃, driedover Na₂SO₄, and concentrated. The residue was partitioned between EtOAc(200 mL) and 1M Na₂CO₃ (50 mL). The solid was kept with the aqueouslayer and the mixture was extracted with EtOAc (50 mL). The aqueouslayer was filtered to give the title compound (8.9 g) after drying invacuo. The combined organic layers were washed with water, brine, driedover Na₂SO₄, and concentrated to give additional title compound (6.5 g).Overall yield of the title compound was 15.4 g, 82%. mp 132-133° C.¹H-NMR (300 MHz, CDCl3) δ 8.15 (d, J=8.4 Hz, 2H), 8.05 (d, J=8.3 Hz,2H), 3.27 (t, 6.6 Hz, 2H), 3.07 (s, 3H), 2.93 (t, J=6.4 Hz, 2H), 2.26(s, 3H); mass spectrum (API-TIS) m/z 255 (MH+). Anal. Calcd. forC₁₂H₁₄O₄S: C, 56.68; H, 5.55; S, 12.61. Found: C, 56.39; 5.40; S, 13.36.

[1901] 11c.1-(5-Methyl-1-(2-methyl-2-sulfanylpropyl)pyrrol-2-yl)-4-(methylsulfonyl)benzene

[1902] The product of Example 11b (2 g, 7.9 mmol), NaOAc (1.3 g, 16mmol), and 1-amino-2-methyl-2-propanethiol.HCl (1.2 g, 8.7 mmol) wereadded to HOAc (15 mL) and heated to 80° C. for 3 hours. The reactionmixture was cooled to room temperature and the HOAc was removed atreduced pressure. The residue was partitioned between EtOAc (40 mL) and1N Na₂CO₃ (15 mL). The organic layer was separated and washed with 1NNa₂CO₃, brine, then dried over Na₂SO₄ and concentrated. The residue wascrystallized from hot MeOH (5 mL) to gave the title compound (1.6 g,63%) as an orange-tan solid. mp 124-126° C. ¹H-NMR (300 MHz, CDCl₃) δ7.93 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz, 2H), 6.22 (d, J=3.6 Hz, 1H),6.03 (d, J=3.6 Hz, 1H), 4.24 (br, 2H), 3.08 (s, 3H), 2.41 (s, 3H), 1,55(s, 1H), 1.04 (s, 6H); mass spectrum (API-TIS) m/z 324 (MH+). 11d.1-(5-Methyl-1-(2-methyl-2-(nitrosothio)propyl)pyrrol-2-yl)-4-(methylsulfonyl)benzene

[1903] The product of Example 11c (100 mg, 0.31 mmol) was dissolved inCH₂Cl₂ and cooled to 0° C. A solution of t-BuONO (40 mL, 31 mmol) inCH₂Cl₂ (1 mL) was added dropwise. After complete addition the reactionmixture was warmed to room temperature and allowed to stir 1 hour. Thesolvent was evaporated and the residue was chromatographed on silica geleluting with 2:1 Hexane:EtOAc. This gave a 1:3 mixture of startingmaterial and desired product (67 mg, 61%). A small fraction of thismixture was reacted with t-BuONO to give the title compound as a darkfoam. ¹H-NMR (300 MHz, CDCl₃) δ 7.89 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.5Hz, 2H), 6.22 (d, J=3.6 Hz, 1H), 6.05 (d, J=3.5 Hz, 1H), 4.60-5.00 (br,2H), 3.15 (s, 3H), 2.39 (s, 3H), 1.6-2.0 (br s, 6H); mass spectrum(API-TIS) m/z 353 (MH+).

Example 12

[1904] 3-(4-(1-Methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3 yl)propyl (2Z)-4-acetyloxy-2-(4-fluorophenyl)-3-(4 (methylsulfonyl)phenyl)but-2-enoate

[1905] 12a.3-(4-Fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-5-hydrofuran-2-one

[1906] This compound was synthesized as described in patent EP 0 788 476B1, (the disclosure of which is incorporated by reference herein in itsentirety), lactone 11. mp 163° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.94 (d,J=8.6 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.38-7.43 (mult, 2H), 7.06-7.27(mult, 2H), 5.18 (s, 2H), 3.08 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 172.5,165.0, 161.7, 153.7, 142.2, 136.3, 131.4, 131.3, 128.6, 128.3, 128.0,125.3, 125.2, 116.4, 116.1, 70.5, 44.4; mass spectrum (API-TIS) m/z 333(MH⁺), 350 (MNH₄ ⁺). Anal. Calcd for C₁₇H₁₃FO₄S: C, 61.44; H, 3.94; F,5.72; S, 9.65. Found: C, 61.24; H, 3.89; F, 5.70; S, 9.52.

[1907] 12b.1-((1Z)-2-(4-Fluorophenyl)-3-hydroxy-1-(hydroxymethyl)prop-1-enyl)-4-(methylsulfonyl)benzene

[1908] A solution of diisobutylaluminium hydride (70.2 mL, 1M solutionin THF, 9.98 g, 70.2 mmol) was added dropwise to a solution of theproduct of Example 12a (4.68 g, 14.1 mmol) in THF (190 mL) at 0° C.After stirring for 30 min at 0° C. and then 1 hour at room temperature,the mixture was cooled to 0° C. Additional DIBAL (30 mL, 1M solution inTHF, 4.27 g, 30 mmol) was added dropwise and stirred for 1 hour at roomtemperature. This reaction mixture was poured into a solution of 1Msodium potassium tartrate (200 mL) containing MeOH (50 mL). The aqueousmixture was extracted with EtOAc. The organic layer was dried overNa₂SO₄, and filtered. The solvent was removed in vacuo to give the titlecompound (4.7 g, 99%) as a colorless oil. ¹H-NMR (300 MHz, MeOH-d₄) δ7.73 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.07-7.12 (mult, 2H),6.85-6.91 (mult, 2H), 4.64 (s, 2H), 4.62 (s, 2H), 3.06 (s, 3H); massspectrum (API-TIS) m/z 337 (MH⁺), 354 (MNH₄ ⁺).

[1909] 12c.(2Z)-3-(4-Fluorophenyl)-4-hydroxy-2-(4-(methylsulfonyl)phenyl)but-2-enylacetate

[1910] Acetic anhydride (1.33 mL, 1.4 g, 14.0 mmol) was added dropwiseto a solution of the product of Example 12b (4.7 g, 14.0 mmol), DMAP (56mg, 0.46 mmol) and triethylamine (5.89 mL, 42.3 mmol) in CH₂Cl₂ (600 mL)at room temperature. The mixture was stirred for 1 hour at roomtemperature, washed with water and dried over Na₂SO₄. The residue, afterevaporation of the solvent, was chromatographed on silica gel elutingwith 1:1 to 3:2 EtOAc:Hexane to give the title compound (1.31 g, 25%) asa colorless oil, followed by its regio-isomer,(2Z)-2-(4-fluorophenyl)-4-hydroxy-3-(4-(methylsulfonyl)phenyl)but-2-enylacetate (1.37 g, 26%) also as a colorless oil.(2Z)-3-(4-fluorophenyl)-4-hydroxy-2-(4-(methylsulfonyl)phenyl)but-2-enylacetate: ¹H-NMR (300 MHz, CDCl₃) δ 7.73 (d, J=8.4 Hz, 2H), 7.21 (d,J=8.5 Hz, 2H), 7.02-7.06 (mult, 2H), 6.80-6.86 (mult, 2H), 5.17 (s, 2H),4.63 (s, 2H), 3.01 (s, 3H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ171.4, 163.6, 160.4, 145.9, 143.6, 139.0, 135.6 (J_(19F-C)=3.4 Hz),134.3, 131.0, 130.9, 130.5, 127.3, 115.5, 115.2, 64.4, 63.4, 44.5, 21.0;mass spectrum (API-TIS) m/z 396 (MNH₄ ⁺).(2Z)-2-(4-Fluorophenyl)-4-hydroxy-3-(4-(methylsulfonyl)phenyl)but-2-enylacetate: ¹H-NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8.4 Hz, 2H), 7.30 (d,J=8.4 Hz, 2H), 6.82-6.97 (mult, 4H), 5.16 (s, 2H), 4.61 (s, 2H), 2.99(s, 3H), 1.99 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 163.4, 160.1,146.8, 141.0, 138.5, 136.7, 134.7 (J_(19F-C)=3.5 Hz), 131.0, 130.9,130.1, 126.9, 115.4, 115.1, 64.4, 62.8, 44.3, 20.8; mass spectrum(API-TIS) m/z 396 (MNH₄ ⁺).

[1911] 12d.(2Z)-3-(4-Fluorophenyl)-2-(4-(methylsulfonyl)phenyl)-4-oxobut-2-enylacetate

[1912] A mixture of the product of Example 12c (1.31 g, 3.47 mmol) andMnO₂ (6.96 g, 80 mmol) in CH₂Cl₂ (175 mL) was stirred for 16 hours atroom temperature and then filtered through a pad of Celite. The filtratewas dried over Na₂SO₄, filtered and concentrated in vacuo to give thetitle compound (0.81 g, 62%) as yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ10.39 (s, 1H), 7.79 (d, J=10.3 Hz, 2H), 7.31 (d, J=12.2 Hz, 2H),6.88-6.91 (mult, 4H), 5.45 (s, 2H), 3.02 (s, 3H), 2.00 (s, 3H); ¹³C NMR(75 MHz, CDCl₃) δ 190.9, 170.4, 164.1, 160.8, 149.6, 143.9, 141.3,140.3, 132.4, 132.3, 130.0, 129.9, 127.4, 115.7, 115.5, 62.1, 44.4,20.7; mass spectrum (AFI-TIS) m/z 394 (MNH₄ ⁺).

[1913] 12e(2Z)-4-Acetyloxy-2-(4-florophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoicacid

[1914] To a solution of the product of Example 12d (0.81 g, 2.15 mmol)and 2-methyl-2-butene (28.9 mL, 19.1 g, 273 mmol) in t-butanol (170 mL),was added a solution of NaClO₂ (4.87 g, 53.9 mmol) and NaH₂PO₄ (4.80 g,40.1 mmol) in water (10 mL). The mixture was stirred for 2 hours at roomtemperature. The residue, after evaporation of. the solvent, wasdissolved in pH=7 buffer solution (250 mL) and extracted with EtOAc. Theaqueous layer was acidified with 10% HCl (˜pH=4-5) and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄ and filtered.The residue after evaporation of the solvent was recrystallized fromEtOAc:Hex:CH₂Cl₂ to give the title compound (0.31 g, 37%) as a whitesolid. mp 187° C. ¹H-NMR (300 MHz, THF-d₈) δ 7.87 (d, J=8.1 Hz, 2H),7.47 (d, J=8.1 Hz, 2H), 7.21-7.25 (mult, 2H), 6.97-7.03 (mult, 2H), 5.35(mult, 2H), 3.08 (s, 3H), 1.97 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.8,169.7, 165.2, 162.0, 144.9, 142.2, 141.9, 137.7, 133.9 (J_(C-F)=3.5 Hz),133.2, 133.1, 131.6, 128.4, 116.3, 116.0, 65.9, 44.5, 20.8; massspectrum (API-TIS) m/z 333 (M−HOAc), 410 (M+NH₄ ⁺). Anal. Calcd forC₁₉H₁₇FO₆S.1/2H₂O: C, 56.85; H, 4.52; F, 4.73; S, 7.99. Found: C, 56.83;H, 4.45; F, 5.07; S, 7.94.

[1915] 12f.2-Amino-3-methyl-3-((2,4,6-trimethoxyphenyl)methylthio)butanoic acid

[1916] A suspension of 2-amino-3-methyl-3-sulfanylbutanoic acid(D-penicillamine) (5.0 g, 34 mmol) in CH₂Cl₂ (150 mL) was cooled to 0°C. Trifluoroacetic acid (54 mL, 703 mmol) was added dropwise over aperiod of 5 min. Then 2,4,6-trimethoxy-benzyl alcohol (6.64 g, 34 mmol)in CH₂Cl₂ (137 mL) was added dropwise at 0° C. with stirring. Stirringwas continued for 1 hour at 0° C. and then for 2 hours at roomtemperature. The solvent was removed in vacuo and the residue was driedunder high vacuum for 3 hours. The crude red solid was recrystallizedfrom 1:1:1 CH₂Cl₂/MeOH/EtOAc to give the title compound (10.5 g, 95%) asa white solid. ¹H-NMR (300 MHz, CDCl₃) δ 6.10 (s, 2H), 3.84 (s, 6H),3.76 (s, 3H), 3.40-4.10 (m, 3H), 1.69 (s, 3H), 1.23 (s, 3H); massspectrum (API-TIS) m/z 330 (MH⁺).

[1917] 12g.2-Amino-3-methyl-3-((2,4,6-trimethoxyphenyl)methylthio)butan-1-ol

[1918] To a stirred solution of the product of Example 12f (10.5 g, 32mmol) in THF (80 mL) was added dropwise lithium aluminum hydride (1 M inTHF, 64 mL, 64 mmol) at 0° C. under nitrogen. The resulting solution wasstirred at 0° C. for 1 hour and then at room temperature for 2 hours.The excess reducing-agent was destroyed by careful portionwise additionof Na₂SO₄.10H₂O at 0° C. The granular white precipitate was filtered andwashed with 30% methanol in CH₂Cl₂. The combined filtrate was dried overNa₂SO₄, filtered and evaporated to give the title compound (7.6 g, 76%)as a yellow oil which was used for the next step without furtherpurification. ¹H-NMR (300 MHz, CDCl₃) δ 6.10 (s, 2H), 3.85 (s, 6H), 3.81(s, 3H), 3.74 (s, 2H), 3.60-3.80 (mult, 2H), 3.37-3.43 (mult, 1H),2.93-2.98 (mult, 1H), 1.45 (s, 3H), 1.30 (s, 3H); mass spectrum(API-TIS) m/z 316 (MH⁺).

[1919] 12h.4-(1-Methyl-1-((2,4,6-trimethoxyphenyl)methylthio)ethyl)-1,3-oxazolidin-2-one

[1920] A mixture of K₂CO₃ (0.33 g, 2.4 mmol), diethylcarbonate (50 mL)and the product of Example 12g (7.6 g, 24 mmol) was heated at 100° C.for 24 hours. Excess diethylcarbonate was evaporated and the resultantlight brown slurry was cooled to room temperature, diluted with CH₂Cl₂and filtered to remove the K₂CO₃. The filtrate was evaporated and theresidue was chromatographed on silica gel eluting with 1:1 EtOAc:Hexaneto give the title compound 2.6 g (32%) as a viscous yellow oil. ¹H-NMR(300 MHz, CDCl₃) δ 6.13 (s, 2H), 6.07 (bs, 1H), 4.30-4.40 (mult, 1H),4.25-4.28 (mult, 1H), 4.03-4.08 (mult, 1H), 3.86 (s, 6H), 3.83 (s, 2H),3.81 (s, 3H), 1.32 (s, 3H), 1.27 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ160.7, 159.5, 158.7, 106.3, 90.9, 66.5, 59.5, 56.0, 55.5, 47.1, 23.8,22.3, 20.3; mass spectrum (API-TIS) m/z 342 (MH⁺), 359 (MNH₄ ⁺).

[1921] 12i. 3-Bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)propane

[1922] t-Butyldimethylchlorosilane (17.4 g, 115 mmol) in dry THF (50 mL)was added dropwise to a solution of 1,3-bromopropanol (16 g, 115 mmol)and imidazole (7.85 g, 115 mmol) in dry THF (50 mL) at room temperature.The resulting white suspension was stirred at room temperature for 16hours. The reaction mixture was diluted with EtOAc (200 mL), washed withwater, brine, dried over Na₂SO₄, filtered, and concentrated in vacuo atroom temperature to give the title compound 28.5 g (98%) as a colorlessvolatile liquid. ¹H-NMR (300 MHz, CDCl₃) δ 3.74 (t, J=5.7 Hz, 2H), 3.52(t, J=6.5 Hz, 2H), 2.02-2.06 (mult, 2H), 0.90 (s, 9H), 0.07 (s, 6H); ¹³CNMR (75 MHz, CDCl₃) δ 60.6, 35.7, 30.8, 26.1, -5.2.

[1923] 12j.4-(1-Methyl-1-((2,4,6-trimethoxyphenyl)methylthio)ethyl)-3-(3-(1,1,2,2-tetramethyl-1-silapropoxy)propyl)-1,3-oxazolidin-2-one

[1924] NaH (0.84 g, 35.3 mmol) was added portionwise to a solution ofthe product of Example 12h (8.03 g, 23.5 mmol) in dry DMF (25 mL) undernitrogen at 0° C. The resulting suspension was stirred at 0° C. for 20min to give a brown red solution. The product of Example 12i (7.14 g,28.2 mmol) in DMF (7 mL) was added dropwise and stirred at roomtemperature for 16 hours and then the solvent was evaporated. Theresidue was treated with 1:1 EtOAc:water and the organic layer wasseparated. The aqueous layer was extracted with EtOAc and the combinedorganic phases were washed with water, dried over Na₂SO₄, and filtered.Evaporation of the solvent left a residue that was chromatographed onsilica gel eluting with 5% to 25% EtOAc:Hexane to give the titlecompound 6.2 g (51%) as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 6.11 (s,2H), 4.38-4.42 (mult, 1H), 4.05-4.11 (mult, 1H), 3.93-3.96 (mult, 1H),3.83 (s, 6H), 3.80 (s, 3H), 3.77 (s, 2H), 3.65 (t, J=6.1 Hz, 2H),3.58-3.71 (mult, 1H), 3.34-3.44 (mult, 1H), 1.66-1.96 (mult, 2H), 1.56(s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.04 (s, 6H); ¹³C NMR (75 MHz,CDCl₃) δ 160.7, 159.5, 158.7, 107.0, 90.8, 65.7, 61.7, 60.6, 55.9, 55.4,48.3, 42.6, 30.3, 26.8, 26.0, 22.2, 20.4, 18.4, −5.3; mass spectrum(API-TIS) m/z 514 (MH⁺).

[1925] 12k.3-(3-Hydroxypropyl)-4-(1-methyl-1-sulfanylethyl)-1,3-oxazolidin-2-one

[1926] The product of Example 12j (5.0 g, 9.75 mmol) was treated withwater (4.0 mL), phenol (4.0 g), anisole (4.0 mL) and finallytrifluoroacetic acid (49 mL). The resultant solution was stirred at roomtemperature for 1 hour. The volatiles were evaporated to give a yellowoil. The crude yellow oil was chromatographed on silica gel eluting with1:1 EtOAc:Hexane to 5% MeOH:CH₂Cl₂ to give the title compound 1.4 g(66%) as a pale yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.30-4.35 (mult,2H), 3.50-3.82 (mult, 5H), 2.80-2.95 (bs, 1H), 1.83-1.89 (mult, 2H),1.78 (s, 1H), 1.42 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.5, 65.8, 65.4,59.2, 47.2, 42.2, 30.1, 29.0, 28.0; mass spectrum (API-TIS) m/z 220(MH⁺), 237 (MNH₄ ⁺). Anal. Calcd for C₉H₁₇NO₃S: C, 49.29; H, 7.81; N,6.39. Found: C, 48.99; H, 7.71; N, 6.04.

[1927] 12l.3-(3-Hydroxypropyl)-4-(1-methyl-1-(nitrosothio)ethyl)-1,3-oxazolidin-2-one

[1928] To a solution of t-BuONO (1.67 mL of 90% solution, 1.32 g, 12.8mmol) in CH₂Cl₂ (10 mL) was added dropwise a solution of the product ofExample 12k (1.4 g, 6.4 mmol) in CH₂Cl₂ (16 mL) at 0° C. The resultinggreen solution was stirred at 0° C. for 1 hour and then at roomtemperature for 20 min in the dark. Evaporation of the solvent gave aresidue that was-chromatographed on silica gel eluting with 1:1EtOAc:CH₂Cl₂ to 5% MeOH:CH₂Cl₂ to give the title compound 0.98 g (62%)as a green oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.61-4.66 (mult, 1H),4.36-4.46 (mult, 2H), 3.42-3.75 (mult, 4H), 2.30-2.45 (br s, 1H), 1.97(s, 3H), 1.96 (s, 3H), 1.74-1.80 (mult, 2H); ¹³C NMR (75 MHz, CDCl₃) δ160.2, 65.3, 63.3, 59.3, 58.8, 42.3, 29.8, 25.4, 25.0; mass spectrum(API-TIS) m/z 219 (M−NO), 249 (MH⁺), 266 (MNH₄ ⁺). Anal. Calcd forC₉H₁₆N₂O₄S: C, 43.54; H, 6.50; N, 11.28. Found: C, 43.61; H, 6.59; N,10.99.

[1929] 12m.3-(4-(1-Methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl)propyl(2Z)-4-acetyloxy-2-(4-flurophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoate

[1930] Bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.14 g, 0.32 mmol)and 4-(dimethylamino)pyridine(19.0 mg, 0.16 mmol) were added to asolution of the product of Example 12l (100 mg, 0.40 mmol) and theproduct of Example 12e (61 mg, 0.16 mmol) in THF (2 mL) at 0° C. Theresulting solution was stirred at 0° C. for 1 hour and then at roomtemperature for 20 hours. Evaporation of the solvent gave a residue thatwas chromatographed on silica gel eluting with 1:1 EtOAc:CH₂Cl₂to givethe title compound 68 mg (70%) as a green foam. ¹H-NMR (300 MHz, CDCl₃)δ 7.78 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H), 6.99-7.03 (mult, 2H),6.82-6.88 (mult, 2H), 5.17 (s, 2H), 4.53-4.57 (mult, 1H), 4.36-4.43 (m,2H), 4.25 (t, J=6.1 Hz, 2H), 3.64-3.74 (mult, 1H), 3.18-3.28 (mult, 1H),3.02 (s, 3H), 1.95 (s, 3H), 1.91 (s, 3H), 1.87 (s, 3H), 1.85-2.06 (mult,2H); mass spectrum (API-TIS) m/z 593 (M-NO), 623 (MH⁺), 640 (MNH₄ ⁺).

Example 13

[1931] (2Z)-3-(4-Fluorophenyl)-3-(N-methyl-N-(2-methyl-2-(nitrosothio)propyl)carbamoyl)-2-(4-(methylsulfonyl)phenyl)prop-2-enyl acetate

[1932] 13a.(2Z)-3-(4-Fluorophenyl)-3-(N-methyl-N-(2-methyl-2-sulfanylpropyl)carbamoyl)-2-(4-(methylsulfonyl)phenyl)prop-2-enylacetate

[1933] Bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.242 g, 0.55 mmol)was added to a solution of the product of Example 12e (0.18 g, 0.46mmol), triethylamine (0.62 mL, 0.45 g, 4.4 mmol) and4-(dimethylamino)pyridine (56 mg, 0.46 mmol) in THF (6 mL) at roomtemperature. After 5 min, 1-amino-2-methyl-2-thiopropane (85.6 mg, 0.55mmol) was added. The resulting mixture was stirred at room temperaturefor 16 hours. The reaction mixture was diluted with EtOAc (50 mL),washed with water, brine, dried over Na₂SO₄, and filtered. Evaporationof the solvent gave a residue that was chromatographed on silica geleluting with 2% MeOH:CH₂Cl₂ to give the title compound (189 mg, 83%) asa white foam. mp 45-47° C. ¹H-NMR (300 MHz, DMSO-d₆) δ 7.44 (d, J=8.4Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.08-7.11 (mult, 4H), 4.95-5.05 (br, s2H), 3.60 (s, 2H), 3.21 (s, 3H), 3.14 (s, 3H), 2.86 (s, 1H), 1.95 (s,3H), 1.33 (s, 6H); ¹³ C NMR (75 MHz, CDCl₃) δ 170.6, 170.2, 160.9,143.9, 141.0, 139.8, 132.7, 131.3, 131.2, 130.6, 127.6, 116.1, 115.8,65.5, 60.6, 46.5, 44.6, 39.4, 31.7, 21.0; mass spectrum (API-TIS) m/z494 (MH⁺).

[1934] 13b.(2Z)-3-(4-Fluorophenyl)-3-(N-methyl-N-(2-methyl-2-(nitrosothio)propyl)carbamoyl)-2-(4-(methylsulfonyl)phenyl)prop-2-enyl acetate

[1935] To a solution of t-BuONO (141 μL of 90% solution, 111 mg, 1.08mmol) in CH₂Cl₂ (1.4 mL) was added dropwise a solution of the product ofExample 13a (163 mg, 0.33 mmol) in CH₂Cl₂ (4.3 mL) at 0° C. Theresulting green solution was stirred at 0° C. for 15 min and at roomtemperature and then for 15 min in the dark. The residue, afterevaporation of the solvent, was chromatographed on silica gel elutingwith 1:1 to 2:1 EtOAc:CH₂Cl₂ to give the title compound 60 mg (35%) as agreen foam. mp 37-38° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.80 (d, J=8.3 Hz,2H), 7.35 (d, J=8.3 Hz, 2H), 7.04-7.08 (mult, 2H), 6.85-6.90 (mult, 2H),4.96 (s, 2H), 4.25 (s, 2H), 3.04 (s, 3H), 2.95 (s, 3H), 2.04 (s, 3H),1.92 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 170.6, 170.5, 164.2, 160.9,143.7, 140.6, 139.8, 133.0, 131.2, 131.1, 130.5, 130.2, 127.5, 116.1,115.8, 65.4, 58.2, 57.8, 44.5, 39.3, 27.9, 20.9; mass spectrum (API-TIS)m/z 493 (M-NO), 523 (MH⁺), 540 (MNH₄ ⁺).

Example 14

[1936] 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethyl(2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoate

[1937] 14a. 2-(1-Methyl-4-(nitrosothio)-4-piperidyl)ethyl(2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoate

[1938] DCC (0.11 g, 0.53 mmol) in CH₂Cl₂ (5 mL) was added dropwise to astirred solution of the product of Example 12e (0.21 g, 0.53 mmol),2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethan-1ol (prepared as describedin Patent Application WO/025776, (the disclosure of which isincorporated by reference herein in its entirety) Example 13d, 0.132 g,0.64 mmol) and 4-(dimethylamino)pyridine (33 mg, 0.27 mmol) in CH₂Cl₂ (5mL) at room temperature. The resulting suspension was stirred at roomtemperature for 16 hours then the precipitate was filtered and washedwith CH₂Cl₂ (10 mL). The combined organic phase was dried over Na₂SO₄and filtered. The residue after evaporation of the solvent waschromatographed on silica gel eluting with 2% MeOH:CH₂Cl₂ to give thetitle compound 13 mg (4%) as a green oil. ¹H-NMR (300 MHz, CDCl₃) δ 7.76(d, J=8.4 Hz, 2H), 7.28 (d, J=9.1 Hz, 2H), 6.94-6.98 (mult, 2H),6.81-6.86 (mult, 2H), 5.15 (s, 2H), 4.42 (t, J=6.7 Hz, 2H), 3.00 (s,3H), 2.68 (t, J=6.8 Hz, 2H), 2.30 (s, 3H), 2.15-2.43 (mult, 8H), 1.93(s, 3H); mass spectrum (API-TIS) m/z 549 (M-NO), 579 (MH⁺).

Example 15

[1939] (3Z)-4-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)but-3-enoic acid

[1940] 15a.(3Z)-4-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)but-3-enoicacid

[1941] This compound was synthesized as described in U.S. Pat. No.5,807,873, (the disclosure of which is incorporated by reference hereinin its entirety), Example 63. ¹H-NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8.2Hz, 2H), 7.40 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4Hz, 2H), 4.03 (q, J=7.1 Hz, 2H), 3.45 (s, 2H), 3.10 (s, 3H), 0.97 (t,J=7.1 Hz, 3H); mass spectrum (API-TIS) m/z 377 (M-CO₂), 423 (MH⁺), 440(MNH₄ ⁺), 445 (MNa⁺).

[1942] 15b. 2-Bromo-1-(1,1,2,2-tetramethyl-1-silapropoxy)ethane

[1943] t-Butyldimethylchlorosilane (21.7 g, 144 mmol) in dry THF (50 mL)was added dropwise to a solution of 1,2-bromoethanol (18 g, 144 mmol)and imidazole (9.81 g, 144 mmol) in dry THF (50 mL) at room temperature.The resulting white suspension was stirred at room temperature for 16hours. The reaction mixture was diluted with EtOAc (200 mL), washed withwater, brine, dried over Na₂SO₄, filtered and concentrated in vacuo atroom temperature to give the title compound 33.2 g (96%) as a colorlessliquid. ¹H-NMR (300 MHz, CDCl₃) δ 3.89 (t, J=6.5 Hz, 2H), 3.39 (t, J=6.6Hz, 2H), 0.90 (s, 9H), 0.10 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 63.7,60.5,33.4,26.0, 21.2,14.3, -5.1.

[1944] 15c.4-(1-Methyl-1-((2,4,6-trimethoxyphenyl)methylthio)ethyl)-3-(2-(1,1,2,2-tetramethyl-1-silapropoxy)ethyl)-1,3-oxazolidin-2-one

[1945] NaH (1.6 g, 66.7 mmol) was added portionwise to a solution of theproduct of Example 12h (15.3 g, 44.9 mmol) in dry DMF (50 mL) undernitrogen at 0° C. The resulting suspension was stirred at 0° C. for 20min to give a brown red solution. The product of Example 15b (12.9 g,53.8 mmol) in DMF (10 mL) was added dropwise and stirred at roomtemperature for 16 hours. The solvent was evaporated. The residue waspartitioned with 1:1 EtOAc:water and the organic layer was separated.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with water, dried over Na₂SO₄, and filtered. Theresidue after evaporation of the solvent was chromatographed on silicagel eluting with 1:1 EtOAc:Hexane to give the title compound (18 g, 80%)as a white foam. ¹H-NMR (300 MHz, CDCl₃) δ 6.12 (s, 2H), 4.38-4.47(mult, 1H), 4.09-4.21 (mult, 3H), 3.83 (s, 9H), 3.79 (s, 2H), 3.71-3.79(mult, 2H), 3.42-3.53 (m, 1H), 1.50 (s, 3H), 1.29 (s, 3H), 0.95 (s, 9H),0.08 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.8, 159.7, 158.9, 106.5,90.9, 65.9, 62.3, 60.5, 56.0, 55.5, 48.6, 47.5, 26.4, 26.0, 22.6, 21.2,20.3, 18.3, 14.4, -5.3; mass spectrum (API-TIS) m/z 500 (MH⁺).

[1946] 15d.3-(2-Hydroxyethyl)-4-(1-methyl-1-sulfanylethyl)-1,3-oxazolidin-2-one

[1947] The product of Example 15c (14.9 g, 29.8 mmol) was treated withwater (11.8 mL), phenol (11.8 g), anisole (11.8 mL) and finallytrifluoroacetic acid (147 mL). The resultant solution was stirred atroom temperature for 1 hour and then the solvent was evaporated to givea yellow oil which was chromatographed on silica gel eluting with 1:1EtOAc:Hexane to 5% MeOH:CH₂Cl₂ to give the title compound 4.2 g (69%) asa pale yellow oil. 1H-NMR (300 MHz, CDCl₃) δ 4.33-4.43 (mult, 2H),3.72-3.92 (mult, 4H), 3.50-3.59 (mult, 1H), 2.55-2.80 (br s, 1H), 1.78(s, 1H), 1.41 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 160.6, 66.2, 66.0,60.4, 48.3, 47.6, 29.0, 27.8; mass spectrum (API-TIS) m/z 206 (MH⁺), 223(MNH₄ ⁺). Anal. Calcd for C₈H,₁₅NO₃S: C, 46.81; H, 7.37; N, 6.82. Found:C, 46.81; H, 7.11; N, 6.61.

[1948] 15e.3-(2-Hydroxyethyl)-4-(1-methyl-1-(nitrosothio)ethyl)-1,3-oxazolidin-2-one

[1949] To a solution of t-butyl nitrite (4.45 mL of 90% solution, 3.5 g,34.1 mmol) in CH₂Cl₂ (28 mL) was added dropwise a solution of theproduct of Example 15d (3.88 g, 18.9 mmol) in CH₂Cl₂ (58 mL) at 0° C.The resulting green solution was stirred at 0° C. for 1 hour and then atroom temperature for 20 min in the dark. The residue after evaporationof the solvent was chromatographed on silica gel eluting with 1:1EtOAc:CH₂Cl₂ to 5% MeOH:CH₂Cl₂ to give the title compound 3.7 g (84%) asa green oil. ¹H-NMR (300 MHz, CDCl₃) δ 4.70-4.74 (mult, 1H), 4.41-4.52(mult, 2H), 3.77-3.89 (mult, 3H), 3.44-3.50 (mult, 1H), 1.99 (s, 3H),1.96 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 160.4, 65.8, 63.9, 60.0, 59.3,48.1, 25.7, 24.8; mass spectrum (API-TIS) m/z 205 (M-NO), 235 (MH⁺), 252(MNH₄ ⁺). Anal. Calcd for C₈H₁₄N₂O₄S: C, 41.02; H, 6.02; N, 11.96.Found: C, 41.30; H, 5.87; N, 11.68.

[1950] 15f.(3Z)-4-(4-Chlorophenyl)-3-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)but-3-enoicacid

[1951] DCC (32 mg, 0.155 mmol) in CH₂Cl₂ (0.5 mL) was added dropwise toa stirred solution of the product of Example 15a (66 mg, 0.155 mmol),the product of Example 15e (36 mg, 0.154 mmol) and4-(dimethylamino)pyridine (19 mg, 0.155 mmol) in CH₂Cl₂ (2 mL) at 0° C.The resulting suspension was stirred at 0° C. for 15 min and then atroom temperature for 1.5 hours. The precipitate was filtered and washedwith CH₂Cl₂ (5 mL). The combined organic phases were dried over Na₂SO₄and filtered. The residue after evaporation of the solvent waschromatographed on silica gel eluting with 1:3 EtOAc:CH₂Cl₂to give thetitle compound 69 mg (70%) as a green solid. mp 40-42° C. ¹H-NMR (300MHz, CDCl₃) δ 7.96 (d, J=6.7 Hz, 2H), 7.39 (d, J=6.6 Hz, 2H), 7.28-7.31(mult, 2H), 7.04-7.07 (mult, 2H), 4.69-4.73 (m, 1H), 4.01-4.47 (m,2H+2H+1H), 3.98 (q, J=7.1 Hz, 2H), 3.42-3.50 (mult, 1H), 3.37 (s, 2H),3.09 (s, 3H), 1.96 (s, 3H), 1.93 (s, 3H), 0.93 (t, J=7.1 Hz, 3H); ¹³CNMR (75 MHz, CDCl₃) δ 170.7, 168.3, 159.1, 149.3. 145.6. 149.7. 139.4,134.6, 130.0, 128.6, 128.0, 126.9, 65.4, 62.6, 61.3, 61.3, 59.1, 44.5,44.3, 37.9, 25.2, 25.1, 13.6; mass spectrum (API-TIS) m/z 609 (M-NO),639 (MH⁺), 659 (MNH₄ ⁺). Anal. Calcd for C₂₈H₃₁ClN₂O₉S₂: C, 52.62; H,4.89; N, 4.38; Cl, 5.55; S, 10.03. Found: C, 52.40; H, 4.98; N, 4.17;Cl, 5.68, S, 9.80.

Example 16

[1952]3-Methyl-N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)-3-(nitrosothio)butanamide

[1953] 16a.3-Methyl-N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)-3-((2,4,6-trimethoxyphenyl)methylthiobutanamide

[1954] 3-Methyl-3-((2,4,6-trimethoxyphenyl)methylthio)butanoic acid(prepared as described in patent application WO 97/34871, (thedisclosure of which is incorporated by reference herein in itsentirety), Example 1a, 1.05 g, 3.37 mmol) was added to a stirredsolution of 4-(5-methyl-3-phenylisoxazol-4-yl)benzene sulfonamide(prepared as described by Talley et. al., J. Med. Chem. 43, 775 (2000),(the disclosure of which is incorporated by reference herein in itsentirety), 0.85 g, 2.70 mmol), 4-(dimethylamino)pyridine (0.1 g) in THF(30 mL). The resulting solution was stirred at room temperature for 15min and then solid DCC (0.84 g, 4.04 mmol) was added. The reactionmixture was stirred at room temperature for 3 hours, the solid was thenremoved by filtration. The filtrate was concentrated and the residue waschromatographed on silica gel eluting with 1:1 EtOAc:Hexane to give thetitle compound (0.92 g, 56%) as a white solid. mp 138-140° C. ¹H-NMR(300 MHz, CDCl₃) δ 9.98 (s, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.25-7.42(mult, 7H), 6.20 (s, 2H), 3.92 (s, 6H), 3.38 (s, 3H), 3.79 (s, 2H), 2.54(s, 2H), 2.45 (s, 3H), 1.20 (s, 6H); ¹³C-NMR (75 MHz, CDCl₃) δ 168.8,167.3, 161.0, 158.5, 138.0, 136.1, 129.8, 129.7, 128.9, 128.7, 128.4,114.5, 105.2, 91.1, 56.1, 55.4, 47.3, 43.8, 29.0, 21.1, 11.7; massspectrum (API-TIS) m/z 611 (MH⁺).

[1955] 16b.3-Methyl-N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)-3-sulfanylbutanamide

[1956] The product of Example 16a (0.6 g, 0.98 mmol) in CH₂Cl₂ (5 mL)was added to a stirred solution of cysteine (1.1 g, 9.07 mmol) in TFA (5mL) and the resulting pale yellow solution was stirred at roomtemperature for 1 hour. Crushed ice (˜3 g) was added and the mixtureneutralized with concentrated NH₄OH (8 mL). The aqueous mixture wasextracted with EtOAc (3×25 mL). The combined organic layers were driedover Na₂SO₄ and concentrated to give the title compound (0.4 g, 95%) asa viscous oil. This material was used in the next reaction withoutfurther purification. mp 138-140° C. ¹H-NMR (300 MHz, CDCl₃) δ 8.05 (d,J=8.3 Hz, 2H), 7.30-7.40 (mult, 7H), 2.57 (s, 2H), 2.49(s, 3H), 2.09 (s,1H), 1.37 (s, 6H); ¹³C-NMR (75 MHz, CDCl₃) δ 168.5, 167.5, 161.1,137.6,136.3, 130.0, 129.7, 128.8,128.7, 128.4, 128.1, 114.4, 52.0, 42.0, 32.4,11.7; mass spectrum (API-TIS), m/z 431 (MH⁺).

[1957] 16c.3-Methyl-N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl)-3-(nitrosothio)butanamide

[1958] A few drops of HCl in ether was added to a stirred solution ofproduct of Example 16b (0.4 g, 0.93 mmol) in CH₂Cl₂ (5 mL) and MeOH (5mL). t -BuONO (90%, 120 mL, 0.93 mmol) was then added. The resultingolive green solution was stirred at room temperature for 15 min undernitrogen. Cold water (25 mL) was added and the product was extractedinto EtOAc (2×25 mL). The organic layer was dried over Na₂SO₄ andconcentrated. Flash chromatography of the residue on silica gel elutingwith 1:1 EtOAc/Hexane gave the title compound (0.32 g, 75%) as a greenfoam. ¹H-NMR (300 MHz, CDCl₃) δ 9.38 (s, 1H), 7.96 (d, J=8.4 Hz, 2H),7.28-7.43 (mult, 7H), 3.22 (s, 2H), 2.52 (s, 3H), 1.98 (s, 6H); ¹³C-NMR(75 MHz, CDCl₃) δ 167.8, 167.6, 161.1, 137.4, 136.2, 130.0, 129.8,128.7,128.5, 128.0, 114.4, 53.6, 48.3, 27.8, 11.6; mass spectrum(API-TIS), m/z 460 (MH⁺).

Example 17

[1959]2-Methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate

[1960] 17a. Methyl5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate

[1961] This compound was prepared as described in Penning et. al. J.Med. Chem. 40, 1347-1365 (1997), (the disclosure of which isincorporated by reference herein in its entirety), Compound 3a. mp 186°C. ¹H-NMR (300 MHz, DMSO-d₆) δ 7.89 (d, J=8.6 Hz, 2H), 7.6-7.4 (m, 6H),7.32 (d, J=8.6 Hz, 2H), 7.21 (s, 1H), 3.87 (s, 3H); mass spectrum(API-TIS) m/z 392 (MH⁺).

[1962] 17b.5-(4-Chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylic acid

[1963] A stirred mixture of the product of Example 17a (9.75 g, 24.9mmol), aqueous NaOH (1.5 N, 60 mL), and THF (200 mL) was heated toreflux for 5 hours. The reaction mixture was concentrated on a rotaryevaporator. The residue was partitioned between EtOAc (200 mL) and 2Naqueous HCl (100 mL). The organic layer was separated and washed withwater, dried over Na₂SO₄, filtered, and concentrated to give a solidmaterial. Crystallization from EtOH/THF (1:1) gave the title compound(8.8 g, 90%) as an off-white solid. mp 203° C. ¹H NMR (300 MHz, DMSO-d₆)δ 8.02 (d, J=8.4 Hz, 2H), 7.7-7.6 (m, 4H), 7.45 (d, J=8.4 Hz, 2H), 7.28(s, 1H); mass spectrum (API-TIS) m/z 378 (MH⁺).

[1964] 17c. 2-methyl-2-sulfanylpropan-1-ol

[1965] To 2-methylpropanal (3.53 g, 49 mmol) in carbon tetrachloride (30ml) was added sulfur monochloride (2 ml, 25 mmol) and the reactionmixture was stirred at 55° C. for 2 hours. After cooling to roomtemperature, the volatiles were evaporated in vacuo to give2-((1,1-dimethyl-2-oxoethyl)disulfanyl)-2-methylpropanal. The disulfide(17.5 g, 85.7 mmol) was dissolved in THF (100 ml) and LiA1H₄ (86 ml,1M/THF) was added slowly. After stirring at room temperature for 1 hour,the mixture was poured onto ice, treated with 3N HCl (150 ml) and thenextracted with EtOAc. The organic extracts were dried over sodiumsulfate and the volatiles were evaporated to yield 12.8 g (71%) of thetitle compound as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.44 (s,2H), 2.25 (brs, 1H), 1.63 (s, 1H), 1.36 (s, 6H); ¹³C NMR (CDCl₃) 73.3,46.3, 28.3.

[1966] 17d. 2-methyl-2-(nitrosothio)propan-1-ol

[1967] To a solution of the product Example 17c (4.4 g, 41.5 mmol) inCH₂Cl₂ (50 ml) was added t-BuONO (5.5 ml, 41.5 mmol). The reactionmixture was stirred at room temperature for 10 minutes and the volatileswere evaporated in vacuo at 40° C. to give 4.6 g (82%) of the titlecompound as a dark green oil. ¹H NMR (300 MHz, CDCl₃) δ 4.17 (s, 2H),1.95 (brs, 1H), 1.90 (s, 6H); ¹³C NMR (CDCl₃) 70.5, 57.7, 25.1.

[1968] 17e.2-Methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)pyrazole-3-carboxylate

[1969] To a stirred solution of the product of Example 17b (3.78 g, 10.0mmol), the product of Example 17d (1.35 g, 10.0 mmol),1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (3.83 g,20.0 mmol), and 4-(dimethylamino)pyridine (10 mg) in DMF (80 mL) wasadded triethylamine (2.79 mL, 20.0 mmol). After being stirred at roomtemperature for 4 hours, the mixture was diluted with EtOAc (200 mL),washed with 1N HCl, water, dried over Na₂SO₄, filtered, andconcentrated. Chromatography of the residue on silica gel eluting with1:4 EtOAc:Hexane gave the title compound (0.20 g, 4%) as a green solid.mp 153° C. (dec). ¹H NMR (300 MHz, DMSO-d₆) δ 7.88 (d, J=8.6 Hz, 2H),7.55-7.49 (m, 4H), 7.32 (d, J=8.6 Hz, 2H), 7.20 (s, 1H), 3.32 (s, 2H),1.82 (s, 6H); mass spectrum (API-TIS) m/z 495 (MH+). Anal. Calcd. forC₂₀H₁₉ClN₄O₅S₂: C, 48.53; H, 3.87; N, 11.32; Cl, 7.16; S, 12.96. Found:C, 48.79; H, 4.12; N, 11.50; Cl, 6.81; S, 12.76.

Example 18

[1970]4-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-((4-((nitroxy)methyl)phenyl)methyl)-2-hydroxypyridazin-3-one

[1971] 18a.4-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-benzyl-2-hydropyridazin-3-one

[1972] This compound was synthesized as described in patent applicationWO 99/10331, (the disclosure of which is incorporated by referenceherein in its entirety), Example 10. m.p. 151-153° C. ¹H -NMR (300 MHz,CDCl₃) δ 7.85 (d, J=8.4 Hz, 2H), 7.83 (m, 1H), 7.53 (m, 2H), 7.31 (m,5H), 7.15 (m, 2H), 6.93 (m, 2H), 5.93 (s, 2H), 3.02 (s, 3H); ¹³C-NMR (75MHz, CDCl₃) δ 164.3, 161.0, 159.5, 140.5, 138.7, 13706, 135.8, 132.5,132:4, 129.9, 129.1, 128.6, 128.1, 127.7, 115.2, 115.2, 56.1; 44.2; massspectrum (API-TIS) m/z 435 (MH⁺).

[1973] 18b.4-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-hydropyridazin-3-one

[1974] To the product of Example 18a (74 mg, 0.17 mmol) in toluene (20mL) was added AlBr₃ (140 mg, 0.52 mmol). The reaction mixture was heatedat 90° C. for 15 minutes and then cooled to 0° C. The reaction mixturewas then poured into ice cold water, acidified with 1 N HCl andextracted with ethyl acetate (2×50 mL). The combined extracts werewashed with water (2×25 mL) and brine (1×25 mL), dried over Na₂SO₄ andfiltered. Evaporation of the solvent gave a residue that was purified bycolumn chromatography on silica gel eluting with 5% methanol in CH₂Cl₂to give the title compound (45 mg, 76%). ¹H NMR (300 MHz, CDCl₃) δ7.8-7.9 (m, 3H), 7.35 (d, J=9 Hz, 2 H), 7.2 (m, 2 H), 7.0 (t, J=9 Hz, 2H), 3.05 (s, 3 H); LRMS (APIMS) m/z 345 (M+H)⁺.

[1975] 18c. Methyl4-((5-(4-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-6-oxohydro-pyridazinyl)methyl)benzoate

[1976] The product of Example 18b (210 mg, 0.61 mmol) was dissolved inanhydrous DMF (3 mL) and then K₂CO₃ (336 mg, 2.44 mmol) was added. Tothis reaction mixture was added methyl 4-(bromomethyl)benzoate (140 mg,0.61 mmol) and the mixture was stirred at room temperature overnight.The reaction mixture was diluted with water (25 mL) and extracted withethyl acetate (2×50 mL). The combined extracts were washed with water(4×50 mL), brine (1×25 mL), and dried over sodium sulfate. Evaporationof the solvent gave a residue that was purified by column chromatographyon silica gel eluting with 1:1 EtOAc:Hexane to gave the title compound(210 mg, 70%) as a colorless foam. ¹H-NMR (300 MHz, CDCl₃) δ 8.02 (d,J=7.8 Hz, 2H), 7.86 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.58 (d, J=7.8 Hz,2H), 7.32 (t, J=7.9 Hz, 2H), 7.15 (t, J=6.8 Hz, 2H), 6.94 (t, J=8.2 Hz,2H), 5.43 (s, 2H), 3.89 (s, 3H), 3.03 (s, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ166.7, 164.5, 159.5, 140.8, 140.7, 140.4, 138.8, 137.4, 137.3, 132.5,132.4, 130.0, 129.9, 129.0, 128.3, 127.8, 127.4, 115.3, 55.8, 52.1,44.3; mass spectrum (API-TIS)) m/z 493 (MH⁺).

[1977] 18d.4-(4-Fluorophenyl)-2-(4-(hydroxymethyl)phenyl)-5-(4-(methylsulfonyl)phenyl)-2-hydroxypyridazin-3-one

[1978] The product of Example 18c (190 mg, 0.386 mmol) was dissolved inanhydrous CH₂Cl₂ (10 mL). The solution was cooled to 0° C. and 1MDIBAL-H (1.05 mL) was added dropwise under nitrogen atmosphere. Thereaction mixture was stirred at 0° C. for 30 minutes and then at roomtemperature for 15 minutes. It was then quenched with ice cold water,acidified with 1 N HCl, and extracted with CH₂Cl₂ (2×50 mL). Thecombined extracts were washed water (2×25 mL), brine (1×25 mL) and thendried over Na₂SO₄. Evaporation of the solvent gave a residue that waspurified by column chromatography on silica gel eluting 5% methanol inCH₂Cl₂ to give the title compound (100 mg, 54%) as a colorless foam. mp155-164° C. ¹H-NMR (CDCl₃) δ 7.86 (d, J=8.2 Hz, 2H), 7.82 (s, 1H), 7.52(d, J=7.8 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.14(t, J=7.6 Hz, 2H), 6.93 (t, J=8.5 Hz, 2H), 5.38 (s, 2H), 4.65 (s, 2H),3.03 (s, 3H); ¹³C-NMR (300 MHz, CDCl₃) δ 164.4, 161.1, 159.5, 140.9,140.7, 140.5, 138.8, 137.2, 135.1, 132.4, 129.9, 129.4, 127.7, 127.6,115.6, 115.3, 64.8, 55.9, 44.3; mass spectrum (API-TIS) m/z 465 (MH⁺).

[1979] 18e.4-(4-Fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-((4-((nitroxy)-methyl)phenyl)methyl)-2-hydroxypyridazin-3-one

[1980] The product of Example 18d (30 mg, 0.065 mmol) was dissolved inanhydrous ethyl acetate (0.5 mL). In a separate flask the nitratingmixture was prepared by adding successively acetic anhydride (472 μL,5.20 mmol) and fuming nitric acid (137 μL, 3.25 mmol) at 0° C. From thismixture, 65 μL was added to the above solution cooled to 0° C. Thereaction mixture was stirred at 0° C. for 5 minutes and quenched withwater and then extracted with ethyl acetate. The organic layer wasseparated, washed with water, brine, and dried over Na₂SO₄. Evaporationof the solvent gave a residue that was purified by preparative thinlayer chromatography (0.25 mm thick silica gel plate) using 6:4EtOAc:Hexane to give the title compound (5.5 mg, 17%) as a white solid.mp 78-87° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.86 (d, J=8.2 Hz, 2H), 7.84 (s,1H), 7.58 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.2 Hz,2H), 7.15 (t, J=6.4 Hz, 2H), 6.95 (t, J=8.6 Hz, 2H), 5.41 (s, 2H), 5.40(s, 2H), 3.04 (s, 3H); mass spectrum (API-TIS) m/z 510 (MH⁺).

Example 19

[1981]4-(Methylsulfonyl)-1-(1-(2-(nitrooxy)ethyl)-4-benzylpyrazol-5-yl)benzene

[1982] 19a. 1-(4-Methylthiophenyl)-3-phenylpropan-1-one

[1983] To a stirred solution of 4-(methylthio)benzonitrile (25.0 g, 0.17mol) in THF (100 mL) under N₂ atmosphere was added phenethylmagnesiumchloride (1.0 M in THF, 210 mL, 0.21 mol). The solution was heated toreflux for 4 hours, cooled to 0° C., and quenched carefully with water(10 mL). The resulting slurry was treated with 6 N hydrochloric acid(200 mL) and stirred at room temperature overnight. The THF wasevaporated from the mixture, and the residue was extracted with EtOAc(2×300 mL). The combined organic extracts were washed with 2M Na₂CO₃,dried over Na₂SO₄, filtered, and concentrated to give a solid material.Recrystallization from EtOAc-Hex (1:4) afforded the title compound (41.5g, 96%) as greenish plates. mp 105° C. ¹H NMR (300 MHz, CDCl₃) δ 7.85(d, J=8.5 Hz, 2H), 7.32-7.19 (m, 7H), 3.24 (t, J=6.8 Hz, 2H), 3.06 (t,J=6.8 Hz, 2H), 2.50 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 198.2, 145.8,141.3, 133.2 128.48, 128.42, 128.38, 126.1, 125.0, 40.2, 30.2, 14.7;mass spectrum (API-TIS) m/z 257 (M+H).

[1984] 19b. Mixture of2-(3-(4-methylthiophenyl)-4-benzylpyrazolyl)ethan-1-ol and2-(5-(4-methylthiophenyl)-4-benzylpyrazolyl)ethan-1-ol

[1985] To a stirred solution of the product of Example 19a (850 mg, 3.3mmol) in THF (8 mL) at −78° C. under N₂ atmosphere was added lithiumdiisopropylamide (1.5 M in cyclohexane, 2.66 mL, 4.0 mmol) dropwise.After 30 min, a solution of HCO₂Et (0.32 mL, 4.0 mmol) in THF (1 mL) wasadded, and the reaction was allowed to gradually warm to roomtemperature and stirred overnight. The mixture was poured into 1 N HCl(10 mL), and extracted with EtOAc (2×20 mL). The combined organicextracts were washed with saturated NaHCO₃ (10 mL), dried over Na₂SO₄,filtered, and concentrated to give an off-white solid (905 mg). Astirred solution of this solid and 2-hydoxyethylhydrazine (0.37 mL, 5.00mmol) in EtOH (15 mL) was heated to reflux under N₂ for 3 hours, andthen concentrated. The residue was dissolved in EtOAc (50 mL), washedwith 1N HCl, dried over Na₂SO₄, filtered, and concentrated. The residuewas chromatographed on silica gel eluting with EtOAc to give tworegioisomeric pyrazoles as an inseparable mixture (0.81 g, 75% over twosteps). Ratio of isomers 3:2 as judged by the proton NMR. ¹H NMR (300MHz, CDCl₃) δ 7.53-7.09 (m, ArH), 4.17 (t, J=4.5 Hz), 4.08 (t, J=4.5Hz), 3.98 (t, J=5.0 Hz), 3.96 (s), 3.91 (t, 5.0 Hz), 3.71 (s), 2.51 (s),2.49 (s); mass spectrum (API-TIS) m/z 325 (M+H).

[1986] 19c and 19d.1-(1-(2-Hydroxyethyl)-4-benzylpyrazol-5-yl)-4-(methylsulfonyl)benzeneand1-(1-(2-Hydroxyethyl)-4-benzylpyrazol-3-yl)-4-(methylsulfonyl)benzene

[1987] The product of Example 19b (810 mg, 2.50 mmol) was dissolved inMeOH (15 mL), and treated with oxone (4.61 g, 7.50 mmol) and water (10ml). The slurry was stirred at room temperature for 30 min. The reactionmixture was poured into water (20 mL), neutralized with aqueous Na₂CO₃,and extracted with EtOAc (50 mL×2). The combined organic extracts weredried over Na₂SO₄, filtered, and concentrated. The residue waschromatographed on silica gel eluting with EtOAc to give first compoundExample 19c (450 mg, 50%) followed by Example 19d (260 mg, 29%).Physical data for Example 19c: R_(f) 0.47 (EtOAc, silica gel). mp 96° C.¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=8.6 Hz, 2H), 7.81 (d, J=8.6 Hz,2H), 7.31-7.17 (m, 6H), 4.23 (t, J=4.5 Hz, 2H), 4.03 (t, J=4.5 Hz, 2H),4.00 (s, 2H), 3.05 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 147.7, 139.9,139.1, 138.8, 131.8, 128.6, 128.3, 128.0, 127.4, 126.3, 118.6, 61.6,54.0, 44.4, 30.7; mass spectrum (API-TIS) m/z 357 (M+H). Anal. calcd forC₁₉H₂₀N₂O₃S: C, 64.02, H, 5.66; N, 7.86, S, 9.00. Found: C, 63.80; H,5.76; N, 8.10; S, 8.98. Physical data for Example 19d: R_(f) 0.38(EtOAc, silica gel). mp 68° C. ¹H NMR (300 MHz, CDCl₃) δ 7.99 (d, J=8.2Hz, 2H), 7.51 (d, J=8.2 Hz, 2H), 7.41 (s, 1H), 7.25-7.14 (m, 3H), 7.06(d, J=7.2 Hz, 2H), 4.07 (t, J=4.6 Hz, 2H), 3.93 (t, J=4.6 Hz, 2H), 3.72(s, 2H), 3.09 (s, 3H); ¹³C NMR (75 Mhz, CDCl₃) δ 140.5, 140.3, 139.6,139.5, 135.3, 130.9, 128.3, 128.1, 127.5, 126.0, 119.1, 61.3, 51.1,44.2, 29.8; mass spectrum (API-TIS) m/z 357 (M+H). Anal. calcd forC₁₉H₂₀N₂O₃S: C, 64.02, H, 5.66; N, 7.86, S, 9.00. Found: C, 64.18; H,5.87; N, 7.79; S, 8.94.

[1988] 19e.4-(Methylsulfonyl)-1-(1-(2-(nitrooxy)ethyl)-4-benzylpyrazol-5-yl)benzene

[1989] Fuming HNO₃ (90%, 1 mL) was added to Ac₂O (5 mL) at 0° C., andthe resulting mixture was stirred for 10 minutes. The product of Example19d (235 mg, 0.66 mmol) in EtOAc (6 mL) was added, and the solution wasstirred at 0° C. for 5 min. The mixture was poured into ice-cooledsaturated NaHCO₃ (10 mL), extracted with EtOAc (2×20 mL). The combinedorganic extracts were repeatedly washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the title product as oil (259 mg,96%). ¹H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4Hz, 2H), 7.24-7.18 (m, 4H), 7.06 (m, 2H), 4.77 (t, J=5.0 Hz, 2H), 4.31(t, J=5.0 Hz, 2H), 3.72 (s, 2H), 3.10 (s, 3H); mass spectrum (API-TIS)m/z 402 (M+H).

Example 20

[1990]4-(1-Cyclohexyl-3-((nitrooxy)methyl)pyrazol-5-yl)-1-methylsulfonyl)benzene

[1991] 20a. Methyl(2Z)-2-hydroxy-4-(4-methylthiophenyl)-4-oxobut-2-enoate

[1992] Dimethyloxalate (26 g, 180.7 mmol) was added to a stirredsuspension of sodium methoxide (9.75 g, 180.7 mmol) in dry toluene (200mL) at 0° C. The white suspension was stirred for 15 min at 0° C. Asolution of 4′-(methylthio)acetophenone (15 g, 90.4 mmol) in dry toluene(150 mL) was then added dropwise over 15 min giving a yellow suspensionwhich was stirred for 2 hours at room temperature. The thick yellowsuspension was transferred to a 2 liter flask and stirred vigorouslywith 10% HCl (250 mL) and EtOAc (200 mL) to dissolve all the solidspresent. The organic layer was separated and the aqueous layer wasextracted with EtOAc (100 mL). The combined organic extracts were washedwith water (250 mL), dried over Na₂SO₄ and the solvent was evaporatedunder reduced pressure to give thick brown oil. The brown oil wasdissolved in CH₂Cl₂ (25 mL) and hexane (125 mL) and left in a freezer at−20° C. for 16 hours to give the title compound (18 g, 79%) as orangecolor solid. mp 81° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.83 (d, J=8.6 Hz, 2H),7.23 (d, J=8.6 Hz, 2H), 6.97 (s, 1H), 3.89 (s, 3H), 2.47 (s, 3H);¹³C-NMR (75 MHz, CDCl₃); mass spectrum (API-TIS) m/z 253 (MH⁺)

[1993] 20b.Methyl-1-cyclohexyl-5-(4-methylthiophenyl)pyrazole-3-carboxylate.

[1994] A mixture of the product of Example 20a (1.98 g, 7.8 mmol) andcyclohexylhydrazine hydrochloride (1.54 g, 10.2 mmol) in methanol (40mL) was heated at 70° C. for 3 hours and cooled to room temperature. Themixture was made basic with 10% Na₂CO₃ and extracted with EtOAc (3×25mL). The organic extracts were dried over Na₂SO₄ and the solvent wasevaporated under reduced pressure to give a thick oil. The oil wasdissolved in CH₂Cl₂ (4 mL) and hexane (20 mL) and left in a freezer at−10° C. for 16 hours to give the title compound (2.2 g, 85%) as a whitesolid. mp 84° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.33 (d, J=8.3 Hz, 2H), 7.26(d, J=8.3 Hz, 2H), 6.76 (s, 1H), 4.08-4.13 (mult, 1H), 3.93 (s, 3H),2.54 (s, 3H), 2.07-2.20 (mult, 2H), 1.80-1.95 (mult, 4H), 1.62-1.72(mult, 1H), 1.20-1.30 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 163.1,143.6, 142.3, 140.1, 129.4, 126.4, 126.2, 108.8, 58.7, 51.9, 33.1, 25.5,24.8, 15.3; mass spectrum (API-TIS), m/z 331 (MH⁺). Anal. calcd forC₁₈H₂₂N₂O₂S: C, 65.43; H, 6.71; N, 8.48; S, 9.70 Found: C, 65.28; H,6.66; N, 8.47; S, 9.61.

[1995] 20c.1-Cyclohexyl-5-(4-methylthiophenyl)pyrazole-3-yl)methan-1-ol.

[1996] A solution of lithium aluminum hydride (2 mL at 1 M, 2 mmol) wasadded to a stirred solution of the product of Example 20b (0.7 g, 2.1mmol) in THF (15 mL) at 0° C. The resulting clear solution was stirredat room temperature for 1 hour. Solid Na₂SO₄.10H₂O (2 g) was added insmall portions with stirring until a thick precipitate formed. Methanolin CH₂Cl₂ (10%, 50 mL) was added and the mixture was filtered. The solidwas washed with additional methanol in CH₂Cl₂ (10%, 50 mL) and thecombined filtrates were evaporated to give the title compound (0.61 g,95%) as a white solid. mp 97° C. ¹H-NMR (300 MHz, CDCl₃) δ 7.31 (d,J=8.3 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 6.20 (s, 1H), 4.71 (d, J=4.8 Hz,2H), 4.00-4.15 (mult, 1H), 2.53 (s, 3H), 1.65-2.10 (mult, 7H), 1.15-1.30(mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 151.0, 143.2, 139.3, 129.3, 127.5,126.3, 104.1, 59.0, 57.7, 33.2, 25.6, 25.1, 15.4; mass spectrum(API-TIS) m/z 303 (MH⁺).

[1997] 20d.4-(1-Cyclohexyl-3-(hydroxymethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

[1998] The product of Example 20c (0.6 g, 2.0 mmol) was dissolved in amixture of MeOH (20 mL) and water (8 mL) and cooled to 0° C. Solid oxone(3 g) was added and the resulting suspension was stirred at 0° C. for 1hr. Water (25 mL) and 15% NH₄OH (25 mL) were added. The mixture wasextracted with EtOAC (3×25 mL) and the organic extracts were dried overNa₂SO₄. The solvent was evaporated under reduced pressure to give whitesolid which was recrystallized from CH₂Cl₂ (5 mL) and hexane (20 mL) togive the title compound (0.62 g, 94%) as a white solid. mp 148° C.¹H-NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8.3 Hz, 2H), 7.56 (d, J=8.3 Hz,2H), 6.31 (s, 1H), 4.73 (s, 2H), 3.90-4.10 (mult, 1H), 3.13 (s, 3H),2.45 (s, 1H, OH), 1.66-2.05 (mult, 7H), 1.10-1.25 (mult, 3H); ¹³C-NMR(75 MHz, CDCl₃) δ 151.4, 141.7, 140.4, 136.5, 129.7, 127.9, 105.0, 59.0,58.2, 44.4, 33.3, 25.6, 25.0; mass spectrum (API-TIS),m/z 335 (MH⁺).

[1999] 20e.4-(1-Cyclohexyl-3-(nitrooxy)methyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene

[2000] Fuming HNO₃ (0.76 mL, 18 mmol) was added to Ac₂O (2.7 mL, 28.8mmol) at 0° C. via syringe and stirred for 5 min at 0° C. The mixturewas then transferred with a pasteur pipette to a stirred suspension ofthe product of Example 20d (1.2 g, 3.6 mmol) in EtOAc (40 mL) at roomtemperature and the mixture was stirred for 45 minutes at roomtemperature. Cold saturated NaHCO₃ (40 mL) was added and shaken well ina separatory funnel. The organic layer was separated and dried overNa₂SO₄. The solvent was evaporated under reduced pressure to afford aviscous oil which was dissolved in CH₂Cl₂ (5 mL) and hexane (25 mL). Theresulting clear solution was left in a freezer at −10° C. for 4 hours togive title compound (1.05 g, 77%) as a yellow solid. mp 104° C. ¹H-NMR(300 MHz, CDCl₃) δ 8.05 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 6.39(s, 1H), 5.50 (s, 2H), 3.95-4.10 (mult, 1H), 3.13 (s, 3H), 1.60-2.10(mult, 7H), 1.15-1.30 (mult, 3H); ¹³C-NMR (75 MHz, CDCl₃) δ 143.1,142.1, 140.7, 136.0, 129.8, 127.9, 107.3, 68.6, 58.6, 44.4, 33.3, 25.5,25.0; mass spectrum (API-TIS) m/z 380 (MH⁺). Anal. calcd for C₁₇H₂N₃O₅S:C, 53.81; H, 5.58; N, 11.07; S, 8.45 Found C, 53.55; H, 5.55; N, 10.83;S, 8.36.

Example 21

[2001] Assay for Ovine COX-1 and COX-2 Activity

[2002] The ovine COX-1 and COX-2 activities and the measurement of theprostaglandin products synthesized were performed using the COXInhibitor Screening Assay (Cayman Chemical, Ann Arbor, Mich., which alsocontained the Prostaglandin Screening EIA Kit, used for prostaglandinquantification). The test compounds were dissolved at 50 times thehighest final reaction concentration in DMSO or any other suitablesolvent as stock solutions. These stock solutions were then diluted inthe same solvent. Eight glass test tubes (13×100 mm) were placed in a37° C. water bath. To each test tube was added 950 μL of reaction buffer(0.1 M Tris-HCl, pH 8.0, containing 5 mM EDTA, and 2 mM phenol), 10 μLof 100 M heme solution, and 10 μL (5 units) of either ovine COX-1 orCOX-2 and the resulting mixture was incubated with the enzyme for 2minutes. Twenty μL of the solvent was added to one tube (100% initialactivity or solvent control) and 20 μL of each dilution of the testcompound was added to one tube each. Each tube was vortexed immediatelyafter the addition. The enzyme was incubated with the inhibitor for 3.5minutes at 37° C. The enzymatic reaction was then initiated by theaddition of 10 μL of freshly prepared 10 mM arachidonic acid(neutralized with KOH), vortexed and then incubated for 2 minutes at 37°C. The reaction was terminated by the addition of 50 μL of 1 M HCl,vortexed and placed at room temperature. One hundred microliters of asaturated stannous chloride solution (50 mg/mL of 0.1 M HCl) was addedand the reaction mixture was allowed to stand at room temperature for atleast 5 minutes.

[2003] The prostaglandins (PG) produced in the reactions were assayed,after a 2,000-fold dilution, using the Prostaglandin Screening EIA Kit(Cayman Chemical, Ann Arbor, Mich.). The assay-contains an antibody withbroad specificity for all the prostaglandin families (PGF, PGE, PGD, andthromboxane B-type) synthesized in the COX-1/COX 2 reactions. Thesynthesized prostaglandin competes with a PG-tagged acetylcholineesterase tracer for binding to the PG antibody. Binding of synthesizedPG lowers the calorimetric development of the Ellman's Reagent (computedas %B/B₀). The actual amount of synthesized PG was interpolated from astandard curve using known amounts of supplied prostaglandin E2 (PGE₂)(PGE₂ concentration vs. %B/B₀). The data generated were themean±standard deviation of triplicate wells in the EIA for a singlereaction at a given inhibitor concentration. A plot of % of control(i.e., the solvent control without inhibitor) vs. test compoundinhibitor concentration for both isoenzymes was used to determine theIC₅₀'s for COX-1 and COX-2 for that test compound. The IC₅₀ for thecompounds are given in Table 1. TABLE 1 IC₅₀ VALUES FOR COX-1 and COX-2COX-1 COX-2 Test Compound IC₅₀ (μM) IC₅₀ (μM) Indomethacin 0.18 0.35Celecoxib 34 0.34 Example 1a 100 3.3 Example 1b 190 10 Example 2a Noinhibition up to 300 24 Example 2b No inhibition up to 300 1.2 Example3e 62 0.006 Example 3g No inhibition up to 300 70 Example 5a Noinhibition up to 300 12 Example 5b No inhibition up to 300 33

[2004] The NSAID, indomethacin, did not show selectivity for eitherCOX-1 or COX-2. Celecoxib, a selective COX-2 inhibitor, used as acontrol, was selective for COX-2. The results show that the nitrosatedcompounds (i.e., Examples 1b, 2b and 5b) have similar COX-2 selectivityas their parent non-nitrosated compound (i.e., Example 1a, 2a and 5arespectively). Hence, nitrosation did not effect the COX-2 inhibitionproperties. The results show that the nitrosylated compound (i.e.,Example 3g) was not as potent as the parent non-nitrosylated compound(i.e., Example 3e). The nitrosylation of the sulfonamide group on theparent COX-2 inhibitor probably effected the COX-2 inhibition propertiesof the nitrosylated compound.

Example 22

[2005] Assay for Human COX-1 and COX-2 activity

[2006] The human COX-1 and COX-2 activities and the measurement of theprostaglandin products synthesized were performed using the COXInhibitor Screening Assay (Cayman Chemical, Ann Arbor, Mich., which alsocontained the Prostaglandin Screening EIA Kit, used for prostaglandinquantification). The test compounds were dissolved at 50 times thehighest final reaction concentration in DMSO or any other suitablesolvent as stock solutions. These stock solutions were then diluted inthe same solvent. Eight glass test tubes (13×100 mm) were placed in a25° C. water bath. To each test tube was added 950 μL of reaction buffer(0.1 M Tris-HCl, pH 8.0, containing 5 mM EDTA, and 2 mM phenol), 10 μLof 100 M heme solution, and 10 μL (5 units) of either human COX-1 orCOX-2 and the resulting mixture incubated with the enzyme for 2 minutes.Twenty μL of the solvent was added to one tube (100% initial activity orsolvent control) and 20 μL of each dilution of the test compound wasadded to one tube each. Each tube was vortexed immediately after theaddition. The enzyme was incubated with the inhibitor for 20 minutes at25° C. The enzymatic reaction was then initiated by the addition of 10μL of freshly prepared 10 mM arachidonic acid (neutralized with KOH),vortexed and then incubated for 2 minutes (or, in some cases asindicated, 30 seconds) at 37° C. The reaction was terminated by theaddition of 50 μL of 1 M HCl, vortexed and placed at room temperature.One hundred microliters of a saturated stannous chloride solution (50mg/mL of 0.1 M HCl) was added and the reaction mixture was allowed tostand at room temperature for at least 5 min.

[2007] The prostaglandins (PG) produced in the reactions were assayed,after a 2,000-fold dilution, using the Prostaglandin Screening EIA Kit(Cayman Chemical, Ann Arbor, Mich.). The assay contains an antibody withbroad specificity for all the prostaglandin families (PGF, PGE, PGD, andthromboxane B-type) synthesized in the COX-1/COX 2 reactions. Thesynthesized prostaglandin competes with a PG-tagged acetylcholineesterase tracer for binding to the PG antibody. Binding of synthesizedPG lowers the colorimetric development of the Ellman's Reagent (computedas %B/B₀). The actual amount of synthesized PG was interpolated from astandard curve using known amounts of supplied prostaglandin E2 (PGE₂)(PGE₂ concentration vs. %B/B₀). The data generated were themean±standard deviation of triplicate wells in the EIA for a singlereaction at a given inhibitor concentration. A plot of % of control(i.e., the solvent control without inhibitor) vs. test compoundinhibitor concentration for both isoenzymes was used to determine theIC₅₀'s for COX-1 and COX-2 for that test compound, when IC₅₀'s werecalculated. The % inhibition for selected concentrations of inhibitorstested are given in Table 2. TABLE 2 % INHIBITION OF HIUMAN COX-1 ANDCOX-2 COX-1 Inhibition COX-2 Inhibition Test Compound (% at 100 μM) (%at 10 μM) Example 2a  0^(a)  65  Example 2b  0^(a) 100  Example 4a89^(b)  69^(b) Example 4b 49^(b)  91^(b) Example 19d 95  100  Example19e  0  100  Example 20d 16   34  Example 20e  0   37 

[2008] The results show that the nitrosated compounds (i.e., Examples2b, 5b, 19e and 20e) have similar or slightly improved COX-2 selectivitycompared to their parent non-nitrosated compound (i.e., Example 2a, 4a,19d and 20d, respectively). Hence, nitrosation did not effect the COX-2inhibition properties and might improve the COX-2 inhibition properties.

Example 23

[2009] Preparation of Rat Aortic Smooth Muscle Rings

[2010] Male Sprague-Dawley rats (Charles River Laboratories (Wilmington,Mass.) were euthanized by intraperiton injection of a high dose ofsodium pentobarbitone (80-100 mg/kg). The thoracic aorta was rapidlyexcised and immediately placed in a Petri dish containing warm (37° C.)oxygenated (95% O₂ and 5% CO₂) Kreb's buffer (composition permillimolar: NaCl (119); KCl (4.69); CaCl₂.H₂O (2.52); MgSO₄.7H₂O (0.57);NaHCO₃ (25); NaH₂PO₄.H₂O (1.01) and glucose (11.1). Under a stereoscopicdissecting microscope, the aorta was cleaned, freed from adhering fatand connective tissues. The tissue was cut into ring segments, eachapproximately 2-3 mm in length.

[2011] For experiments to measure relaxation of the tissue under variousconditions, a stainless steel tissue holder and an U-shaped stainlesssteel wire were inserted into the lumen of the aortic ring. The tissueholder anchored the ring at the bottom of the organ bath whereas the endof the U-shaped steel wire was tied with fine silk thread so that itconnected to the FT-202 transducer. The tissue holder and the steel wirealong with the aortic ring were then suspended in a 5-mL double-jacketedtemperature-controlled glass organ bath (Radnoti Glass Technology, Inc.,Monrovia, Calif.) filled with fresh Kreb's buffer. A mixture of 95% O₂and 5% CO₂ was bubbled through a porous sintered disc at the bottom ofthe bath. The rings were given an initial resting tension of 1.5 g andthe preparation was allowed to equilibrate at the initial tension forabout 90 minutes. During this equilibration period, the bath fluid waschanged every 15 minutes and replaced with fresh prewarmed (37° C.)Kreb's buffer. The isometric tension of the aortic muscle at rest andits response to different stimuli were recorded on a Power Macintosh6100 computer via a MacLab 8/S computer interface (CB Sciences, Inc,Milford, Mass.) after an initial amplification through a low-noiseETH-400 bioamplifier (CB Sciences, Inc, Milford, Mass.). Contractileresponsiveness of the tissue strips was established with 10 μMphenylephrine and the strips were incubated with the drug for 20 minutesto establish a steady level of contraction. To test the relaxationeffects, test compounds were added to the phenylephrine-precontractedstrips in the tissue bath at cumulative concentrations of 0.1 μM to 0.1mM. Concentration of test compounds was increased only after relaxationat the previous concentration had reached a plateau level.

Example 24

[2012] Relaxation of Aortic Smooth Muscle Ring by Example 1

[2013] The tissue was prepared according to Example 23. The percentcontraction of phenylephrine-contracted aortic smooth muscle ringsinduced by isosorbide dinitrate (ISDN), Example 1a and Example 1b(nitrate) was measured. FIG. 1 shows that the parent non-nitrosatedcompound, Example 1a, did not relax the aortic ring. The nitrosatedcompound, Example 1b, induced the relaxation of the aortic ring. Theobserved relaxation was more potent than that obtained by the nitratecompound, isosorbide dinitrate.

Example 25

[2014] Relaxation of Aortic Smooth Muscle Ring by Example 2

[2015] The tissue was prepared according to Example 23. The percentcontraction of phenylephrine-contracted aortic smooth muscle ringsinduced by isosorbide dinitrate (ISDN), Example 2a and Example 2b(nitrate) was measured. FIG. 2 shows that the parent non-nitrosatedcompound, Example 2a, did not relax the aortic ring. The nitrosatedcompound, Example 2b, induced the relaxation of the aortic ring. Theobserved relaxation was similar to that obtained by the nitratecompound, isosorbide dinitrate.

Example 26

[2016] Relaxation of Aortic Smooth Muscle Ring by Example 3

[2017] The tissue was prepared according to Example 23. The percentcontraction of phenylephrine-contracted aortic smooth muscle ringsinduced by S-nitrosoglutathione (GSNO), Example 3e and Example 3h(nitrosothiol) was measured. FIG. 3 shows that the parentnon-nitrosylated compound, Example 3e, did not relax the aortic ring.The nitrosylated compound, Example 3h, induced the relaxation of theaortic ring. The observed relaxation was similar to that obtained by thenitrosothiol compound, S-nitrosoglutathione.

Example 27

[2018] Relaxation of Aortic Smooth Muscle Ring by Example 20

[2019] The tissue was prepared according to Example 23. The percentcontraction of phenylephrine-contracted aortic smooth muscle ringsinduced by isosorbide dinitrate (ISDN), Example 20d and Example 20e(nitrate) was measured. FIG. 4 shows that the parent non-nitrosylatedcompound, Example 20d, did not relax the aortic ring. The nitrosatedcompound, Example 20e, induced the relaxation of the aortic ring. Theobserved relaxation was similar to that obtained by the nitratecompound, isosorbide dinitrate.

Example 28

[2020] Anti-Inflammatory Paw Edema Test for Example 2

[2021] The carrageenan-induced rat paw edema test was used to measureantiinflammatory activity. The paw edema test was performed according tothe method of Winter et al, Proc. Soc. Exp. Biol. Med. 111: 544-547,1962. Male Sprague-Dawley rats (200-250 g) were fasted for 24 hours withwater ad libitum. The rats were dosed intragastrically with testcompounds in a volume of 5 mL/kg. One hour after dosing the paw volumewas measured. Then each rat received a subplantar injection of 50 μl of1% suspension of carrageenan. Three hours later, the paw volume wasmeasured and compared with the initial volume measured immediately aftercarrageenan injection. The increase in paw volume is presented as themean±SEM for 5 rats per group. Data were analyzed by performing an ANOVAtest followed by a Student-Keuls post hoc test.

[2022]FIG. 5 shows that the parent non-nitrosated compound Example 2a,the nitrosated compound Example 2b and Celecoxib all reduced the pawvolume and, hence, these compounds have antiinflammatory activity. Thus,nitrosation did not effect the COX-2 inhibition properties of thecompounds.

[2023] The disclosure of each patent, patent application and publicationcited or described in the present specification is hereby incorporatedby reference herein in its entirety.

[2024] Although the invention has been set forth in detail, one skilledin the art will appreciate that numerous changes and modifications canbe made to the invention, and that such changes and modifications can bemade without departing from the spirit and scope of the presentinvention.

What is claimed is:
 1. A compound of Formula (III) or a pharmaceuticallyacceptable salt thereof:

wherein: R¹ is: (a) —S(O)₂—CH₃; (b) —S(O)₂—NR⁸(D¹); (c)—S(O)₂—N(D¹)—C(O)—CF₃; (d) —S(O)—(NH)—NH(D¹); (e)—S(O)—(NH)—N(D¹)—C(O)—CF₃; (f) —P(O)(CH₃)NH(D¹); (g) —P(O)(CH₃)₂; (h)—C(S)—NH(D¹); (i) —S(O)(NH)CH₃; (j) —P(O)(CH₃)OD¹; or (k)—P(O)(CH₃)NH(D¹); R² is: (a) lower alkyl; (b) cycloalkyl; (c) mono-, di-or tri-substituted phenyl or naphthyl, wherein the substituents are eachindependently: (1) hydrogen; (2) halo; (3) alkoxy; (4) alkylthio; (5)CN; (6) haloalkyl; (7) lower alkyl; (8) N₃; (9) —CO₂D¹; (10) —CO₂-loweralkyl; (11) —(C (R⁵)(R⁶))_(z)—OD¹; (12) —(C(R⁵)(R⁶))_(z),—O-lower alkyl;(13) lower alkyl-CO₂—R⁵; (14) —OD¹; (15) haloalkoxy; (16) amino; (17)nitro; (18) alkylsulfinyl; or (19) heteroaryl; (d) mono-, di- ortri-substituted heteroaryl, wherein the heteroaryl is a monocyclicaromatic ring of 5 atoms, said ring having one heteroatom which is S, O,or N, and, optionally, 1, 2, or 3 additional N atoms; or the heteroarylis a monocyclic ring of 6 atoms, said ring having one heteroatom whichis N, and, optionally, 1, 2, 3, or 4 additional N atoms; wherein thesubstituents are each independently: (1) hydrogen; (2) halo; (3) loweralkyl; (4) alkoxy; (5) alkylthio; (6) CN; (7) haloalkyl; (8) N₃; (9)—C(R⁵)(R⁶)—OD¹; (10) —C(R⁵)(R⁶)—O-lower alkyl; or (11) alkylsulfinyl;(e) benzoheteroaryl which includes the benzo fused analogs of (d); (f)—NR¹⁰R¹¹; (g) —SR¹¹; (h) —OR¹¹; (i) —R¹¹; (j) alkenyl; (k) alkynyl; (l)unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl,wherein the substituents are each independently: (1) halo; (2) alkoxy;(3) alkylthio; (4) CN; (5) haloalkyl; (6) lower alkyl; (7) N₃; (8)—CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R¹²)(R¹³)—OD¹; (11)—C(R¹²)(R¹³)—O-lower alkyl; (12) lower alkyl-CO₂—R¹²; (13) benzyloxy;(14) —O-(lower alkyl)-CO₂R¹²; (15) —O-(lower alkyl)-NR¹²R¹³; or (16)alkylsulfinyl; (m) mono-, di-, tri- or tetra-substitutedheterocycloalkyl group of 5, 6 or 7 members, or a benzoheterocycle,wherein said heterocycloalkyl or benzoheterocycle has 1 or 2 heteroatomsselected from O, S, or N and, optionally, a carbonyl group or a sulfonylgroup, and wherein said substituents are each independently: (1) halo;(2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7)N₃; (8) —C(R¹²)(R¹³)—OD¹; (9) —C(R¹²)(R¹³)—O-lower alkyl; or (10)alkylsulfinyl; (n) styryl, mono or di-substituted styryl, wherein thesubstituent are each independently: (1) halo; (2) alkoxy; (3) alkylthio;(4) CN; (5) haloalkyl; (6) lower alkyl; (7) N₃; (8) —CO₂D¹; (9)—CO₂-lower alkyl; (10) —C(R¹²)(R¹³)—OD¹; (11) —C(R¹²)(R¹³)—O-loweralkyl; (12) lower alkyl-CO₂—R¹²; (13) benzyloxy; (14) —O-(loweralkyl)-CO₂R¹²; or (15) —O-(lower alkyl)-NR¹²R¹³; (o) phenylacetylene,mono- or di-substituted phenylacetylene, wherein the substituents areeach independently: (1) halo; (2) alkoxy; (3) alkylthio; (4) CN; (5)haloalkyl; (6) lower alkyl; (7) N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl;(10) —C(R¹²)(R¹³)—OD¹; (11) —C(R¹²)(R¹³)—O-lower alkyl; (12) loweralkyl-CO₂—R¹²; (13) benzyloxy; (14) —O-(lower alkyl)-CO₂R¹²; or (15)—O-(lower alkyl)-NR¹²R¹³; (p) fluoroalkenyl; (q) mono- or di-substitutedbicyclic heteroaryl of 8, 9 or 10 members, consisting of 2, 3, 4 or 5heteroatoms, wherein at least one heteroatom resides on each ring ofsaid bicyclic heteroaryl, said heteroatoms are each independently O, Sand N and said substituents are each independently: (1) hydrogen; (2)halo; (3) lower alkyl; (4) alkoxy; (5) alkylthio; (6) CN; (7) haloalkyl;(8) N₃; (9) —C(R⁵)(R⁶)—OD¹; or (10) —C(R⁵)(R⁶)—O-lower alkyl; (r) K; (s)aryl; (t) arylalkyl; (u) cycloalkylalkyl; (v) —C(O)R¹¹; (u) hydrogen;(v) arylalkenyl; (w) arylalkoxy; (x) alkoxy; (y) aryloxy; (z)cycloalkoxy; (aa) arylthio; (bb) alkylthio; (cc) arylalkylthio; or (dd)cycloalkylthio; X³ is: (a) —C(O)—U—D¹; (b) —CH₂—U—D¹; (c) —CH₂—C(O)—CH₃;(d) —CH₂—CH₂—C(O)—U—D¹; (e) —CH₂—O—D¹²; or (f) —C(O)H Y³is: (a)—(CR⁵(R⁵′))_(k)—U—D¹; (b) —CH₃; (c) —CH₂OC(O)R⁶; or (d) —C(O)H;alternatively, X³ and Y³ taken together are—CR⁸²(R⁸³)—CR^(82′)(R^(83′))—; R⁸², R^(82′), R⁸³ and R^(83′) are eachindependently: (a) hydrogen; (b) hydroxy; (c) alkyl; (d) alkoxy; (e)lower alkyl-OD¹; (f) alkylthio; (g) CN; (h) —C(O)R⁸⁴; or (i) —OC(O)R⁸⁵;R⁸⁴ is: (a) hydrogen; (b) lower alkyl; or (c) alkoxy; R⁸⁵ is: (a) loweralkyl; (b) alkoxy (c) unsubstituted, mono-, di- or tri-substitutedphenyl or pyridyl, wherein the substituents are each independently: (1)halo; (2) alkoxy; (3) haloalkyl; (4) CN; (5) —C(O)R⁸⁴; (6) lower alkyl;(7) —S(O)_(o)-lower alkyl; or (8) —OD¹; alternatively, R⁸² and R⁸³ orR^(82′) and R^(83′) taken together are: (a) oxo; (b) thial; (c)=CR⁸⁶R⁸⁷; or (d) =NR⁸⁸; R⁸⁶ and R⁸⁷ are each independently: (a)hydrogen; (b) lower alkyl; (c) lower alkyl-OD¹; (d) CN; or (e) —C(O)R⁸⁴;R⁸⁸ is: (a) OD¹; (b) alkoxy; (c) lower alkyl; or (d) unsubstituted,mono-, di- or tri-substituted phenyl or pyridyl, wherein thesubstituents are each independently: (1) halo; (2) alkoxy; (3)haloalkyl; (4) CN; (5) —C(O)R^(m); (6) lower alkyl; (7) —S(O)_(o)-loweralkyl; or (8) —OD¹; R⁵and R⁵′ are each independently: (a) hydrogen; (b)amino; (c) CN; (d) lower alkyl; (e) haloalkyl; (f) alkoxy; (g)alkylthio; (h) Q; (i) —O—Q; (j) —S—Q; (k) K; (l) cycloalkoxy; (m)cycloalkylthio; (n) unsubstituted, mono-, or di-substituted phenyl orunsubstituted, mono-, or di-substituted benzyl, wherein the substituentsare each independently: (1) halo; (2) lower alkyl; (3) alkoxy; (4)alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8) Q; (9) nitro; or (10)amino; (o) unsubstituted, mono-, or di-substituted heteroaryl orunsubstituted, mono-, or di-substituted heteroarylmethyl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or the heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or4 additional N atoms; said substituents are each independently: (1)halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl;(7) N₃; (8) —C(R⁶)(R⁷)—OD¹. (9) —C(R⁶)(R⁷)—O-lower alkyl; or (10)alkylsulfinyl (p) —CON(R⁸)(R⁸); (q) —CH₂OR⁸; (r) —CH₂OCN; (s)unsubstituted or substituted: (1) lower alkyl-Q; (2) —O-lower alkyl-Q;(3) —S-lower alkyl-Q; (4) lower alkYl-O-lower alkyl-Q; (5) loweralkyl-S-lower alkyl-Q; (6) lower alkyl-O—Q; (7) lower alkyl-S—Q; (8)lower alkyl-O—K; (9) lower alkyl-S—K; (10) lower alkyl-O—V; or (11)lower alkyl-S—V; wherein the substituent(s) resides on the lower alkyl;(t) cycloalkyl; (u) aryl; (v) arylalkyl; (w) cycloalkylalkyl; (x)aryloxy; (y) arylalkoxy; (z) arylalkylthio; (aa) cycloalkylalkoxy; (bb)heterocycloalkyl; (cc) alkylsulfonyloxy; (dd) alkylsulfonyl; (ee)arylsulfonyl; (ff) arylsulfonyloxy; (gg) —C(O)R¹⁰; (hh) nitro; (ii)amino; (jj) aminoalkyl; (kk) —C(O)-alkyl-heterocyclic ring; (ll) halo;(mm) heterocyclic ring; (nn) —CO₂D¹; (oo) carboxyl; (pp) amidyl; or (qq)alkoxyalkyl; alternatively, R⁵ and R^(5′) taken together with the carbonto which they are attached are: (a) cycloalkyl; or (b) heterocyclicring; R⁶ and R⁷ are each independently: (a) hydrogen; (b) unsubstituted,mono- or di-substituted phenyl; unsubstituted, mono- or di-substitutedbenzyl; unsubstituted, mono- or di-substituted heteroaryl; mono- ordi-substituted heteroarylmethyl, wherein said substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)CN; (6) haloalkyl; (7) N₃; (8) —C(R¹⁴)(R¹⁵)—OD¹; or (9)—C(R¹⁴)(R¹⁵)—O-lower alkyl; (c) lower alkyl; (d) —CH₂OR⁸; (e) CN; (f)—CH₂CN; (g) haloalkyl; (h) —CON(R⁸)(R⁸); (i) halo; or (j) —OR⁸; R⁸is:(a) hydrogen; (b) K; or (c) R⁹; alternatively, R⁵ and R⁵′, R⁶ and R⁷ orR⁷ and R⁸ together with the carbon to which they are attached form asaturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; and optionally up totwo heteroatoms selected from oxygen, S(O)_(o) or NR_(i); R⁹ is: (a)lower alkyl; (b) lower alkyl-CO₂D¹; (c) lower alkyl-NHD¹; (d) phenyl ormono-, di- or tri-substituted phenyl, wherein the substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) CO₂D¹; or (9)haloalkyl; (e) benzyl, mono-, di- or tri-substituted benzyl, wherein thesubstituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7)CN; (8) -CO₂D¹; or (9) haloalkyl; (f) cycloalkyl; (g) K; or (h) benzoyl,mono-, di-, or trisubstituted benzoyl, wherein the substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)lower alkyl-CO₂D¹; (6) lower alkyl-NHD¹; (7) CN; (8) —CO₂D¹; or (9)haloalkyl; R¹⁰ is: (a) hydrogen; or (b) R¹¹; R¹¹ is: (a) lower alkyl;(b) cycloalkyl; (c) unsubstituted, mono-, di- or tri-substituted phenylor naphthyl, wherein the substituents are each independently: (1) halo;(2) alkoxy; (3) alkylthio; (4) CN; (5) haloalkyl; (6) lower alkyl; (7)N₃; (8) —CO₂D¹; (9) —CO₂-lower alkyl; (10) —C(R¹²)(R¹³)—OD¹; (11)—C(R¹²)(R¹³)—O-lower alkyl; (12) lower alkyl-CO₂D¹; (13) loweralkyl-CO₂R¹²; (14) benzyloxy; (15) —O-(lower alkyl)-CO₂D¹; (16)—O-(lower alkyl)-CO₂R²; or (17) —O-(lower alkyl)-NR¹²R¹³; (d)unsubstituted, mono-, di- or tri-substituted heteroaryl, wherein theheteroaryl is a monocyclic aromatic ring of 5 atoms, said ring havingone heteroatom which is S, O, or N, and, optionally, 1, 2, or 3additional N atoms; or said heteroaryl is a monocyclic ring of 6 atoms,said ring having one heteroatom which is N, and, optionally 1, 2, or 3additional N atoms, and wherein said substituents are eachindependently: (1) halo; (2) lower alkyl; (3) alkoxy; (4) alkylthio; (5)CN; (6) haloalkyl; (7) N₃; (8) —C(R¹²)(R¹³)—OD¹; or (9)—C(R¹²)(R¹³)—O-lower alkyl; (e) unsubstituted, mono- or di-substitutedbenzoheterocycle, wherein the benzoheterocycle is a 5, 6, or 7-memberedring with 1 or 2 heteroatoms independently selected from O, S, or N,and, optionally, a carbonyl group or a sulfonyl group, wherein saidsubstituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8)—C(R¹²)(R¹³)—OD¹; or (9) —C(R¹²)(R¹³)—O-lower alkyl; (f) unsubstituted,mono- or di-substituted benzocarbocycle, wherein the carbocycle is a 5,6, or 7-membered ring has optionally a carbonyl group, wherein saidsubstituents are each independently: (1) halo; (2) lower alkyl; (3)alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) N₃; (8)—C(R¹²)(R¹³)—OD¹; or (9) —C(R¹²)(R¹³)—O-lower alkyl; (g) hydrogen; or(h) K R¹² and R¹³ are each independently: (a) hydrogen; (b) lower alkyl;or (c) aryl; or R¹² and R¹³ together with the atom to which they areattached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms; R¹⁴and R¹⁵ are each independently: (a) hydrogen; or (b) lower alkyl; or R¹⁴and R¹⁵ together with the atom to which they are attached form acarbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6 or 7atoms; D¹ is: (a) hydrogen or (b) D; D is: (a) V; or (b) K; U is: (a)oxygen; (b) sulfur; or (c) —N(R_(a))R_(i)—; V is: (a) —NO; (b) —NO₂; or(c) hydrogen K isW_(aa)—E_(b)—(C(R_(e))(R_(f)))_(p)—E_(c)—(C(R_(e))(R_(f)))_(x)—W_(d)—(C(R_(e))(R_(f)))_(y)—W_(i)—E_(j)—W_(g)—(C(R_(e))(R_(f)))_(z)—U—V;wherein aa, b, c, d, g, i and j are each independently an integer from 0to 3; p, x, y and z are each independently an integer from 0 to 10; W ateach occurrence is independently: (a) —C(O)—; (b) —C(S)—; (c) —T—; (d)—(C(R_(e))(R_(f)))_(h)—; (e) alkyl; (f) aryl; (g) heterocyclic ring; (h)arylheterocyclic ring, or (i) —(CH₂CH₂O)_(q)—; E at each occurrence isindependently: (a) —T—; (b) alkyl; (c) aryl; (d)—(C(R_(e))(R_(f)))_(h)—; (e) heterocyclic ring; (f) arylheterocyclicring; or (g) —(CH₂CH₂O)_(q)—; h is an integer form 1 to 10; q is aninteger from 1 to 5; R_(e) and R_(f) are each independently: (a)hydrogen; (b) alkyl; (c) cycloalkoxy; (d) halogen; (e) hydroxy; (f)hydroxyalkyl; (g) alkoxyalkyl; (h) arylheterocyclic ring; (i)cycloalkylalkyl; (j) heterocyclicalkyl; (k) alkoxy; (l) haloalkoxy; (m)amino; (n) alkylamino; (o) dialkylamino; (p) arylamino; (q) diarylamino;(r) alkylarylamino; (s) alkoxyhaloalkyl; (t) haloalkoxy; (u) sulfonicacid; (v) alkylsulfonic acid; (w) arylsulfonic acid; (x) arylalkoxy; (y)alkylthio; (z) arylthio; (aa) cyano; (bb) aminoalkyl; (cc) aminoaryl;(dd) alkoxy; (ee) aryl; (ff) arylalkyl; (gg) carboxamido; (hh)alkylcarboxamido; (ii) arylcarboxamido; (jj) amidyl; (kk) carboxyl; (ll)carbamoyl; (mm) alkylcarboxylic acid; (nn) arylcarboxylic acid; (oo)alkylcarbonyl; (pp) arylcarbonyl; (qq) ester; (rr) carboxylic ester;(ss) alkylcarboxylic ester; (tt) arylcarboxylic ester; (uu) haloalkoxy;(vv) sulfonamido; (ww) alkylsulfonamido; (xx) arylsulfonamido; (yy)alkylsulfonyl, (zz) alkylsulfonyloxy, (aaa) arylsulfonyl, (bbb)arylsulphonyloxy (ccc) sulfonic ester; (ddd) carbamoyl; (eee) urea;(fff) nitro; or (ggg) —U—V; or R_(e) and R_(f) taken together are: (a)oxo; (b) thial; or R_(e) and R_(f) taken together with the carbon towhich they are attached are: (a) heterocyclic ring; (b) cycloalkylgroup; or (c) bridged cycloalkyl group; k is an integer from 1 to 2; Tat each occurrence is independently: (a) a covalent bond, (b) carbonyl,(c) an oxygen, (d) —S(O)_(o)—; or (e) —N(R_(a))R_(i)—; o is an integerfrom 0 to 2; Q is: (a) —C(O)—U—D¹; (b) —CO₂-lower alkyl; (c)tetrazolyl-5-yl; (d) —C(R7)(R⁸)(S—D¹); (e) —C(R⁷)(R⁸)(O—D¹); or (f)—C(R⁷)(R⁸)(O-lower alkyl); R_(a) is: (a) a lone pair of electron; (b)hydrogen; or (c) lower alkyl; R_(i) is: (a) hydrogen; (b) alkyl; (c)aryl; (d) alkylcarboxylic acid; (e) arylcarboxylic acid; (f)alkylcarboxylic ester; (g) arylcarboxylic ester; (h) alkylcarboxamido;(i) arylcarboxamido; (j) alkylsulfinyl; (k) alkylsulfonyl; (l)alkylsulfonyloxy, (m) arylsulfinyl; (n) arylsulfonyl; (o)arylsulphonyloxy; (p) sulfonamido; (q) carboxamido; (r) carboxylicester; (s) aminoalkyl; (t) aminoaryl; (u) —CH₂—C(U—V)(R_(e))(R_(f)); (v)a bond to an adjacent atom creating a double bond to that atom; or (w)—(N₂O₂—)⁻.M⁺, wherein M⁺ is an organic or inorganic cation; with theproviso that the compound of Formula III must contain at least onenitrite, nitrate, thionitrite or thionitrate group.
 2. A compositioncomprising the compound of claim 1 and a pharmaceutically acceptablecarrier.
 3. A method for treating or reducing inflammation, pain orfever in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 4. A method for treating a gastrointestinal disorder, or improvingthe gastrointestinal properties of a COX-2 inhibitor in a patient inneed thereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 2. 5. The method of claim4, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.6. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 2. 7. The method of claim 6, whereinthe wound is an ulcer.
 8. A method for treating or reversing renaltoxicity in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 9. A method for treating a disorder resulting from elevated levels ofCOX-2 in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim2.
 10. The method of claim 9, wherein the disorder resulting fromelevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis,menstrual cramps, premature labor, tendinitis, bursitis, a skin-relatedcondition, neoplasia, an inflammatory process in a disease, anophthalmic disorder, pulmonary inflammation, a central nervous systemdisorder, allergic rhinitis, respiratory distress syndrome, endotoxinshock syndrome, atherosclerosis, a microbial infection, a cardiovasculardisorder, a urinary disorder, a urological disorder, endothelialdysfunction, organ deterioration, tissue deterioration, or activation,adhesion and infiltration of neutrophils at the site of inflammation.11. The method of claim 10, wherein the neoplasia is a brain cancer, abone cancer, an epithelial cell-derived neoplasia (epithelialcarcinoma), a basal cell carcinoma, an adenocarcinoma, agastrointestinal cancer, a lip cancer, a mouth cancer, an esophagealcancer, a small bowel cancer, a stomach cancer, a colon cancer, a livercancer, a bladder cancer, a pancreas cancer, an ovary cancer, a cervicalcancer, a lung cancer, a breast cancer, a skin cancer, a squamus cellcancer, a basal cell cancer, a prostate cancer, a renal cell carcinoma,a cancerous tumor, a growth, a polyp, an adenomatous polyp, a familialadenomatous polyposis or a fibrosis resulting from radiation therapy.12. The method of claim 10, wherein the central nervous system disorderis cortical dementia, Alzheimer's disease, vascular dementia,multi-infarct dementia, pre-senile dementia, alcoholic dementia, seniledementia, or central nervous system damage resulting from stroke,ischemia or trauma.
 13. A method for inhibiting platelet aggregation ina patient in need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 2. 14. Thecomposition of claim 2, further comprising at least one therapeuticagent.
 15. The composition of claim 14, wherein the therapeutic agent isa steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenaseinhibitor, a leukotriene B₄ receptor antagonist, a leukotriene A₄hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutarylcoenzyme A inhibitor, a H₂ receptor antagonist, an antineoplastic agent,an antiplatelet agent, a decongestant, a diuretic, a sedating ornon-sedating anti-histamine, an inducible nitric oxide synthaseinhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, aproton pump inhibitor, an isoprostane inhibitor, or a mixture of two ormore thereof.
 16. The composition of claim 15, wherein the nonsteroidalantiinflammatory compound is acetaminophen, aspirin, diclofenac,ibuprofen, ketoprofen or naproxen.
 17. A method for treating or reducinginflammation, pain or fever in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim
 14. 18. A method for treating a gastrointestinaldisorder, or improving the gastrointestinal properties of a COX-2inhibitor in a patient in need thereof comprising administering to thepatient a therapeutically effective amount of the composition of claim14.
 19. The method of claim 18, wherein the gastrointestinal disorder isan inflammatory bowel disease, Crohn's disease, gastritis, irritablebowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, ableeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis,Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterialinfection, short-bowel (anastomosis) syndrome, or a hypersecretory stateassociated with systemic mastocytosis or basophilic leukemia andhyperhistaminemia.
 20. A method for facilitating wound healing in apatient in need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim
 14. 21. Themethod of claim 20, wherein the wound is an ulcer.
 22. A method fortreating or reversing renal toxicity in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 23. A method for treating adisorder resulting from elevated levels of COX-2 in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim
 14. 24. The method of claim23, wherein the disorder resulting from elevated levels of COX-2 isangiogenesis, arthritis, asthma, bronchitis, menstrual cramps, prematurelabor, tendinitis, bursitis, a skin-related condition, neoplasia, aninflammatory process in a disease, an ophthalmic disorder, pulmonaryinflammation, a central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, a microbial infection, a cardiovascular disorder, aurinary disorder, a urological disorder, endothelial dysfunction, organdeterioration, tissue deterioration, or activation, adhesion andinfiltration of neutrophils at the site of inflammation.
 25. The methodof claim 24, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 26. The method of claim 24,wherein the central nervous system disorder is cortical dementia,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 27. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim
 14. 28. A composition comprising atleast one compound of claim 1 and at least one compound that donates,transfers or releases nitric oxide, or induces the production ofendogenous nitric oxide or endothelium-derived relaxing factor, or is asubstrate for nitric oxide synthase.
 29. The composition of claim 28,further comprising a pharmaceutically acceptable carrier.
 30. Thecomposition of claim 28, wherein the compound that donates, transfers,or releases nitric oxide, or induces the production of endogenous nitricoxide or endothelium-derived relaxing factor or is a substrate fornitric oxide synthase is an S-nitrosothiol.
 31. The composition of claim30, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine,S-nitroso-captopril, S-nitroso-N-acetylpenicillamine,S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, orS-nitroso-cysteinyl-glycine.
 32. The composition of claim 30, whereinthe S-nitrosothiol is: (i) HS(C(R_(e))(R_(f)))_(mm)SNO; (ii)ONS(C(R_(e))(R_(f)))_(mm)R_(e); or (iii)H₂N—CH(CO₂H)—(CH₂)_(mm)—C(O)NH—CH(CH₂SNO)—C(O)NH—CH₂—CO₂ H; wherein mmis an integer from 2 to 20; R_(e) and R_(f) are each independently ahydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, anhydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, acycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino,an alkylamino, a dialkylamino, an arylamino, a diarylamino, analkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, asulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, anarylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, anaminoaryl, an alkoxy, an aryl, an arylalkyl, a carboxamido, aalkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, acarbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, analkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, asulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl,an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a carbamoyl, aurea, a nitro, —T—Q—, or (C(R_(e))(R_(f)))_(k)—T—Q, or R_(e) and R_(f)taken together are an oxo, a methanthial, a heterocyclic ring, acycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO₂; and Tis independently a covalent bond, a carbonyl, an oxygen, —S(O)_(o)—or—N(R_(a))R_(i)—, wherein o is an integer from 0 to 2, R_(a) is a lonepair of electrons, a hydrogen or an alkyl group; R_(i) is a hydrogen, analkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, analkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, anarylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, analkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl,a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, anaminoaryl, —CH₂—C(T—Q)(R_(e))(R_(f)), or —(N₂O₂—)³¹ .M⁺, wherein M+is anorganic or inorganic cation; with the proviso that when R_(i) is—CH₂—C(T—Q)(R_(e))(R_(f)) or —(N₂O₂—).M⁺; then “—T—Q” can be a hydrogen,an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxygroup or an aryl group.
 33. The composition of claim 28, wherein thecompound that donates, transfers, or releases nitric oxide, or inducesthe production of endogenous nitric oxide or endothelium-derivedrelaxing factor, or is a substrate for nitric oxide synthase isL-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine,nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylatedN-hydroxy-L-arginine, citrulline, ornithine, glutamine, or an arginaseinhibitor.
 34. The composition of claim 28, wherein the compound thatdonates, transfers, or releases nitric oxide, or induces the productionof endogenous nitric oxide or endothelium-derived relaxing factor, or isa substrate for nitric oxide synthase is: (i) a compound that comprisesat least one ON—O—, ON—N—or ON—C-group; (ii) a compound that comprisesat least one O₂N—O-, O₂N—N-, O₂N—S- or —O₂N—C-group; (iii) aN-oxo-N-nitrosoamine having the formula: R¹R²N—N(O—M⁺)—NO, wherein R¹and R² are each independently a polypeptide, an amino acid, a sugar, anoligonucleotide, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or aheterocyclic group, and M⁺ is an organic or inorganic cation.
 35. Thecomposition of claim 34, wherein the compound comprising at least oneON—O—, ON—N—or ON—C-group is an ON—O-polypeptide, an ON—N-polypeptide,an ON—C-polypeptide, an ON—O-amino acid, an ON—N-amino acid, anON—C-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—C-sugar, anON—O-oligonucleotide, an ON—N-oligonucleotide, an ON—C-oligonucleotide,a straight or branched, saturated or unsaturated, substituted orunsubstituted, aliphatic or aromatic ON—O-hydrocarbon, a straight orbranched, saturated or unsaturated, substituted or unsubstituted,aliphatic or aromatic ON—N-hydrocarbon, a straight or branched,saturated or unsaturated, substituted or unsubstituted, aliphatic oraromatic ON—C-hydrocarbon, an ON—O-heterocyclic compound, anON—N-heterocyclic compound or a ON—C-heterocyclic compound.
 36. Thecomposition of claim 34, wherein compound comprising at least oneO₂N—O—, O₂N—N—, O₂N—S—or O₂N—C-group is an O₂N—O-polypeptide, anO₂N—N-polypeptide, an O₂N—S-polypeptide, an O₂N—C-polypeptide, anO₂N—O-amino acid, O₂N—N-amino acid, O₂N—S-amino acid, an O₂N—C-aminoacid, an O₂N—O-sugar, an O₂N—N-sugar, O₂N—S-sugar, an O₂N—C-sugar, anO₂N—O-oligonucleotide, an O₂N—N-oligonucleotide, anO₂N—S-oligonucleotide, an O₂N—C-oligonucleotide, a straight or branched,saturated or unsaturated, aliphatic or aromatic, substituted orunsubstituted O₂N—O-hydrocarbon, a straight or branched, saturated orunsaturated, aliphatic or aromatic, substituted or unsubstitutedO₂N—N-hydrocarbon, a straight or branched, saturated or unsaturated,aliphatic or aromatic, substituted or unsubstituted O₂N—S-hydrocarbon, astraight or branched, saturated or unsaturated, aliphatic or aromatic,substituted or unsubstituted O₂N—C-hydrocarbon, an O₂N—O-heterocycliccompound, an O₂N—N-heterocyclic compound, an O₂N—S-heterocyclic compoundor an O₂N—C-heterocyclic compound.
 37. The composition of claim 28,further comprising at least one therapeutic agent.
 38. The compositionof claim 37, wherein the therapeutic agent is a steroid, a nonsteroidalantiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B₄receptor antagonist, a leukotriene A₄ hydrolase inhibitor, a 5-HTagonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H₂receptor antagonist, an antineoplastic agent, an antiplatelet agent, adecongestant, a diuretic, a sedating or non-sedating anti-histamine, aninducible nitric oxide synthase inhibitor, an opioid, an analgesic, aHelicobacter pylori inhibitor, a proton pump inhibitor, an isoprostaneinhibitor, or a mixture of two or more thereof.
 39. The composition ofclaim 38, wherein the nonsteroidal antiinflammatory compound isacetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen or naproxen.40. A method for treating or reducing inflammation, pain or fever in apatient in need thereof comprising administering to the patient atherapeutically effective amount of the composition of claim 29 or 37.41. A method for treating a gastrointestinal disorder, or improving thegastrointestinal properties of a COX-2 inhibitor in a patient in needthereof comprising administering to the patient a therapeuticallyeffective amount of the composition of claim 29 or
 37. 42. The method ofclaim 41, wherein the gastrointestinal disorder is an inflammatory boweldisease, Crohn's disease, gastritis, irritable bowel syndrome,ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer,gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellisonsyndrome, gastroesophageal reflux disease, a bacterial infection,short-bowel (anastomosis) syndrome, or a hypersecretory state associatedwith systemic mastocytosis or basophilic leukemia and hyperhistaminemia.43. A method for facilitating wound healing in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 29 or
 37. 44. The method of claim 43,wherein the wound is an ulcer.
 45. A method for treating or reversingrenal toxicity in a patient in need thereof comprising administering tothe patient a therapeutically effective amount of the composition ofclaim 29 or
 37. 46. A method for treating a disorder resulting fromelevated levels of COX-2 in a patient in need thereof comprisingadministering to the patient a therapeutically effective amount of thecomposition of claim 29 or
 37. 47. The method of claim 46, wherein thedisorder resulting from elevated levels of COX-2 is angiogenesis,arthritis, asthma, bronchitis, menstrual cramps, premature labor,tendinitis, bursitis, a skin-related condition, neoplasia, aninflammatory process in a disease, an ophthalmic disorder, pulmonaryinflammation, a central nervous system disorder, allergic rhinitis,respiratory distress syndrome, endotoxin shock syndrome,atherosclerosis, a microbial infection, a cardiovascular disorder, aurinary disorder, a urological disorder, endothelial dysfunction, organdeterioration, tissue deterioration, or activation, adhesion andinfiltration of neutrophils at the site of inflammation.
 48. The methodof claim 47, wherein the neoplasia is a brain cancer, a bone cancer, anepithelial cell-derived neoplasia (epithelial carcinoma), a basal cellcarcinoma, an adenocarcinoma, a gastrointestinal cancer, a lip cancer, amouth cancer, an esophageal cancer, a small bowel cancer, a stomachcancer, a colon cancer, a liver cancer, a bladder cancer, a pancreascancer, an ovary cancer, a cervical cancer, a lung cancer, a breastcancer, a skin cancer, a squamus cell cancer, a basal cell cancer, aprostate cancer, a renal cell carcinoma, a cancerous tumor, a growth, apolyp, an adenomatous polyp, a familial adenomatous polyposis or afibrosis resulting from radiation therapy.
 49. The method of claim 47,wherein the central nervous system disorder is cortical dementia,Alzheimer's disease, vascular dementia, multi-infarct dementia,pre-senile dementia, alcoholic dementia, senile dementia, or centralnervous system damage resulting from stroke, ischemia or trauma.
 50. Amethod for inhibiting platelet aggregation in a patient in need thereofcomprising administering to the patient a therapeutically effectiveamount of the composition of claim 29 or
 37. 51. A kit comprising atleast one compound of claim
 1. 52. The kit of claim 51, furthercomprising (i) at least one compound that donates, transfers or releasesnitric oxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase; (ii) at least one therapeutic agent; or (iii) at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase and at least onetherapeutic agent.
 53. The kit of claim 52, wherein the at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase; the at least onetherapeutic agent; or the at least one compound that donates, transfersor releases nitric oxide, induces the production of endogenous nitricoxide or endothelium-derived relaxing factor, or is a substrate fornitric oxide synthase and at least one therapeutic agent; are in theform of separate components in the kit
 54. A kit comprising thecomposition of claim 14, 29 or
 37. 55. A compound selected from thegroup consisting of ethyl(2Z)-3-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoateor a pharmaceutically acceptable salt thereof;(2Z)-3-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoic acid or a pharmaceutically acceptable salt thereof;(2Z)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)-N-(2-methyl-2-(nitrosothio)propyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enamideor a pharmaceutically acceptable salt thereof;3-(4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl)propyl(2Z)-4-acetyloxy-2-(4-flurophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoate or a pharmaceutically acceptable salt thereof;(2Z)-3-(4-fluorophenyl)-3-(N-methyl-N-(2-methyl-2-(nitrosothio)propyl)carbamoyl)-2-(4-(methylsulfonyl)phenyl)prop-2-enyl acetate or apharmaceutically acceptable salt thereof;2-(1-methyl-4-(nitrosothio)-4-piperidyl)ethyl(2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoateor a pharmaceutically acceptable salt thereof; and(3Z)-4-(4-chlorophenyl)-3-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)but-3-enoicacid or a pharmaceutically acceptable salt thereof.
 56. A compositioncomprising at least one compound of claim 55 and a pharmaceuticallyacceptable carrier.
 57. The composition of claim 56, further comprising(i) at least one compound that donates, transfers or releases nitricoxide, induces the production of endogenous nitric oxide orendothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase; (ii) at least one therapeutic agent; or (iii) at least onecompound that donates, transfers or releases nitric oxide, induces theproduction of endogenous nitric oxide or endothelium-derived relaxingfactor, or is a substrate for nitric oxide synthase and at least onetherapeutic agent.
 58. A kit comprising at least one compound of claim55.